ENA NUCLEIC ACID PHARMACEUTICALS CAPABLE OF MODIFYING SPLICING OF mRNA PRECURSORS

ABSTRACT

Oligonucleotides having a nucleotide sequence complementary to nucleotide numbers such as 2571-2607, 2578-2592, 2571-2592, 2573-2592, 2578-2596, 2578-2601 or 2575-2592 of the dystrophin cDNA (Gene Bank accession No. NM_004006.1) and therapeutic agents for muscular dystrophy comprising such oligonucleotides.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a division of U.S. Ser. No. 13/673,466, whichis a division of U.S. Ser. No. 12/847,237, filed Jul. 30, 2010, which isa division of U.S. Ser. No. 10/536,258, filed Dec. 13, 2005, which is aNational Stage (371) of PCT/JP03/14915, filed Nov. 21, 2003, and claimspriority to JP 2003-204381, filed Jul. 31, 2003, and JP 2002-340857,filed Nov. 25, 2002.

TECHNICAL FIELD

The present invention relates to ENA nucleic acid pharmaceuticalscapable of modifying splicing of mRNA precursors. More specifically, thepresent invention relates to antisense oligonucleotide compounds tosplicing enhancer sequences within exon 19, 41, 45, 46, 44, 50, 55, 51or 53 of the dystrophin gene, as well as therapeutic agents for musculardystrophy comprising the compounds.

BACKGROUND ART

Muscular dystrophy, which is a genetic muscular disease, is roughlyclassified into Duchenne muscular dystrophy (DMD) and Becker musculardystrophy (BMD). DMD is the most frequently occurring genetic musculardisease and occurs at a ratio of 1 per 3,500 male births. DMD patientsshow symptoms of weakening of muscles in their childhood; thereafter,muscular atrophy progresses consistently and results in death at the ageof around 20. Currently, there is no effective therapeutic for DMD.Development of therapeutics is strongly demanded by DMD patientsthroughout the world. BMD in many cases occurs in adulthood and most ofthe patients are capable of normal survival though slight weakening ofmuscles is observed. Mutations of deletions in the dystrophin gene havebeen identified in ⅔ of DMD and BMD cases. The progress of clinicalsymptoms in DMD or BMD patients is predictable depending on whether suchdeletions disrupt the translational reading frame of mRNA or maintainthat reading frame (Monaco A. P. et al., Genomics 1988: 2:90-95).Although molecular biological understanding of DMD has been thusdeepened, no effective method for treating DMD has been established yet.

When DMD patients have a frame shift mutation, dystrophin proteindisappears completely from patients' skeletal muscles. On the otherhand, dystrophin protein is produced from in-frame mRNA in BMDpatient-derived muscle tissues, though the protein is incomplete. As amethod for treating DMD, there is known a method in which an out-framemutation (the reading frame of amino acids is shifted) is converted toan in-frame mutation (the reading frame is maintained) by modifyingdystrophin mRNA (Matsuo M., Brain Dev 1996; 18:167-172). Recently, ithas been reported that the mdx mouse synthesized a deletion-containingdystrophin as a result of induction of exon skipping with anoligonucleotide complementary to the splicing consensus sequence of thedystrophin gene (Wilton S. D. et al., Neuromusc Disord 1999: 9:330-338;Mann C. J. et al., Proc Natl Acad Sci USA 2001: 98:42-47). In thesestudies, exon skipping is induced using as a target the splicingconsensus sequence located on the border between two exons.

It is asserted that splicing is regulated by splicing enhancer sequences(SESs). In fact, it has been demonstrated that by disrupting the SESwithin exon 19 of the dystrophin gene with an antisense oligonucleotidecomplementary thereto, complete skipping of exon 19 occurs in normallymphoblastoid cells (Takeshima Y. et al., J Clin Invest 1995:95:515-520; Pramono Z. A. et al., Biochem Biophys Res Commun 1996:226:445-449).

It has been also reported that by introducing an oligonucleotidecomplementary to the SES within exon 19 of the dystrophin gene tothereby induce exon skipping, a deletion-containing dystrophin wassuccessfully produced in muscular cells derived from DMD patientscarrying exon 20 deletion (Takeshima Y. et al., Brain & Development2001: 23:788-790; Japanese Unexamined Patent Publication No. H11-140930;Japanese Unexamined Patent Publication No. 2002-10790). This indicatesthat repairing of the reading frame shift by inducing exon 19 skippingwith an antisense oligonucleotide complementary to the SES within exon19 of the dystrophin gene results in production of a dystrophin proteinwhose function is partially restored; and thus it is possible to changeDMD to BMD. If it is possible to convert DMD, a severe myoatrophy, toslight BMD, prolonging patients' lives can be expected.

At present, oligonucleotide analogues having stable and excellentantisense activity are being developed (Japanese Unexamined PatentPublication No. 2000-297097).

It is an object of the present invention to provide therapeutics withbroader applicable range and higher efficacy, by improving antisenseoligonucleotides to the SES within exon 19, 41, 45, 46, 44, 50, 55, 51or 53 of the dystrophin gene.

DISCLOSURE OF THE INVENTION

As a result of extensive and intensive researches toward the achievementof the above-described object, the present inventors have succeeded indesigning and synthesizing those nucleotide sequences and antisenseoligonucleotide compounds which have higher exon skipping effect on exon19, 41, 45, 46, 44, 50, 55, 51 or 53 of the dystrophin gene. Thus, thepresent invention has been achieved.

The present invention may be summarized as follows.

[1] An oligonucleotide having the nucleotide sequence as shown in anyone of SEQ ID NOS: 2-6, 10-22, 30-78, 87 or 88 in the SEQUENCE LISTING,or a pharmacologically acceptable salt thereof.[2] The oligonucleotide of [1] above or a pharmacologically acceptablesalt thereof, wherein at least one of the sugars and/or the phosphatesconstituting the oligonucleotide is modified.[3] The oligonucleotide of [2] above or a pharmacologically acceptablesalt thereof, wherein the sugar constituting the oligonucleotide isD-ribofuranose and the modification of the sugar is modification of thehydroxyl group at position 2′ of D-ribofuranose.[4] The oligonucleotide of [3] above or a pharmacologically acceptablesalt thereof, wherein the modification of the sugar is 2′-O-alkylationand/or 2′-O,4′-C-alkylenation of the D-ribofuranose.[5] The oligonucleotide of [2] above or a pharmacologically acceptablesalt thereof, wherein the modification of the phosphate is thioation ofthe phosphate group.[6] A compound represented by the following general formula (I) or apharmacologically acceptable salt thereof:

(I) B_(T)-B_(M)-B_(B)where B_(T) is a group represented by any one of the following (1a) to(1k):

(1a) HO-, (1b) HO-Bt-, (1c) HO-Bc-Bt-, (1d) HO-Bg-Bc-Bt-, (1e)HO-Ba-Bg-Bc-Bt-, (1f) HO-Bg-Ba-Bg-Bc-Bt-, (1g) HO-Bt-Bg-Ba-Bg-Bc-Bt-,(1h) HO-Bc-Bt-Bg-Ba-Bg-Bc-Bt-, (1j) HO-Bc-Bc-Bt-Bg-Ba-Bg-Bc-Bt-, or (1k)HO-Bg-Bc-Bc-Bt-Bg-Ba-Bg-Bc-Bt-;where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M) is a group represented by the following formula (2):

(2) (SEQ ID NO: 2) -Bg-Ba-Bt-Bc-Bt-Bg-Bc-Bt-Bg-Bg-Bc-Ba-Bt-Bc-Bt-where Bg, Ba, Bt and Bc are as defined above;B_(B) is a group represented by any one of the following (2a) to (2h):

(2a)- CH₂CH₂OH, (2b)- Bt-CH₂CH₂OH, (2c)- Bt-Bg-CH₂CH₂OH, (2d)-Bt-Bg-Bc-CH₂CH₂OH, (2e)- Bt-Bg-Bc-Ba-CH₂CH₂OH, (2f)-Bt-Bg-Bc-Ba-Bg-CH₂CH₂OH, (2g)- Bt-Bg-Bc-Ba-Bg-Bt-CH₂CH₂OH, or (2h)-Bt-Bg-Bc-Ba-Bg-Bt-Bt-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (I) has 2′-O,4′-C-alkylene group.[7] The compound according to claim 6 which is selected from the groupconsisting of the following compounds (i) to (vi), or apharmacologically acceptable salt thereof:(i) a compound where B_(T) is a group represented by (1k) and B_(B) is agroup represented by (2h),(ii) a compound where B_(T) is a group represented by (1a) and B_(B) isa group represented by (2a),(iii) a compound where B_(T) is a group represented by (1a) and B_(B) isa group represented by (2h),(iv) a compound where B_(T) is a group represented by (1e) and B_(B) isa group represented by (2a),(v) a compound where B_(T) is a group represented by (1k) and B_(B) is agroup represented by (2a),(vi) a compound where B_(T) is a group represented by (1a) and B_(B) isa group represented by (2f), and(vii) a compound where B_(T) is a group represented by (1a) and B_(B) isa group represented by (2d).[8] The compound of [6] above which is selected from the groupconsisting of the following compounds (I1) to (I7), or apharmacologically acceptable salt thereof:

(I1) (SEQ ID NO: 1) HO-Bg**-Bc**-Bc**-Bt**-Bg**-Ba*-Bg*-Bc*-Bt*-Bg*-Ba*-Bt*-Bc*-Bt*-Bg*-Bc*-Bt*-Bg*-Bg*-Bc*-Ba*-Bt*-Bc*-Bt*-Bt*-Bg*-Bc**-Ba**-Bg**-Bt**-Bt**-CH₂CH₂OH (I2) (SEQ ID NO: 2)HO-Bg**-Ba**-Bt**-Bc**-Bt**-Bg*-Bc*-Bt*-Bg*-Bg*-Bc**-Ba**-Bt**-Bc**-Bt**-CH₂CH₂OH (I3) (SEQ ID NO: 3)HO-Bg**-Ba**-Bt**-Bc**-Bt**-Bg*-Bc*-Bt*-Bg*-Bg*-Bc*-Ba*-Bt*-Bc*-Bt*-Bt*-Bg*-Bc**-Ba**-Bg**-Bt**- Bt**-CH₂CH₂OH (I4) (SEQID NO: 4) HO-Ba*-Bg**-Bc**-Bt**-Bg**-Ba*-Bt**-Bc*-Bt*-Bg*-Bc*-Bt*-Bg*-Bg**-Bc**-Ba*-Bt**-Bc**-Bt**-CH₂CH₂OH (I5) (SEQ ID NO: 5)HO-Bg**-Bc**-Bc**-Bt**-Bg**-Ba*-Bg*-Bc*-Bt*-Bg*-Ba*-Bt*-Bc*-Bt*-Bg*-Bc*-Bt*-Bg*-Bg**-Bc**-Ba*-Bt**-Bc**-Bt**-CH₂CH₂OH (I6) (SEQ ID NO: 6)HO-Bg**-Ba*-Bt**-Bc**-Bt**-Bg**-Bc*-Bt*-Bg*-Bg*-Bc*-Ba*-Bt*-Bc*-Bt**-Bt**-Bg**-Bc**-Ba*- Bg**-CH₂CH₂OH (I7) (SEQ IDNO: 4) HO-Ba**-Bg**-Bc**-Bt**-Bg**-Ba**-Bt**-Bc**-Bt**-Bg**-Bc**-Bt**-Bg**-Bg**-Bc**-Ba**-Bt**- Bc**-Bt**-CH₂CH₂OH (I8)(SEQ ID NO: 7) HO-Bg**-Ba**-Bt**-Bc**-Bt**-Bg*-Bc*-Bt*-Bg*-Bg*-Bc*-Ba*-Bt*-Bc**-Bt**-Bt**-Bg**-Bc**- CH₂CH₂OH (I9) (SEQ ID NO: 2)HO-Bg**-Ba**-Bt**-Bc**-Bt**-Bg**-Bc**-Bt**-Bg**-Bg**-Bc**-Ba**-Bt**-Bc**-Bt**-CH₂CH₂OHwhere Bg* is a group represented by the following formula (G1^(a)), Ba*is a group represented by the following formula (A1^(a)); Bc* is a grouprepresented by the following formula (C1^(a)); Bt* is a grouprepresented by the following formula (U1^(a)); Bg** is a grouprepresented by formula (G2); Ba** is a group represented by formula(A2); Bc** is a group represented by formula (C2); and Bt** is a grouprepresented by formula (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

and R¹ is individually and independently an alkyl group with 1-6 carbonatoms.)[9] The compound of [8] above where X in formulas (G1^(a)), (A1^(a)),(C1^(a)) and (U1^(a)) is a group represented by formula (X2) and X informulas (G2), (A2), (C2) and (T2) is a group represented by formula(X1), or a pharmacologically acceptable salt thereof.[10] The compound of [8] above where X in all the formulas (G1^(a)),(A1^(a)), (C1^(a)), (U1^(a)), (G2), (A2), (C2) and (T2) is a grouprepresented by formula (X2), or a pharmacologically acceptable saltthereof.[11] The compound of [8] above which is represented by any one of thefollowing formulas (I1-a), (I2-a), (I3-a), (I4-a), (I5-a), (I6-a),(I7-a), (I8-a) and (I9-a), or a pharmacologically acceptable saltthereof:

(I1-a) (SEQ ID NO: 1)

(I2-a) (SEQ ID NO: 2)

(I3-a) (SEQ ID NO: 3)

(I4-a) (SEQ ID NO: 4)

(I5-a) (SEQ ID NO: 5)

(I6-a) (SEQ ID NO: 6)

(I7-a) (SEQ ID NO: 4)

(I8-a) (SEQ ID NO: 7)

(I9-a) (SEQ ID NO: 2)

where Bg* is a group represented by formula (G1^(a)); Ba* is a grouprepresented by formula (A1^(a)); Bc* is a group represented by formula(C1^(a)); Bt* is a group represented by formula (U1^(a)); Bg** is agroup represented by formula (G2); Ba** is a group represented byformula (A2); Bc** is a group represented by formula (C2); Bt** is agroup represented by formula (T2); and in individual formulas, at leastone of Bg*, Ba*, Bc*, Bt*, Bg**, Ba**, Bc** and Bt** has a grouprepresented by formula (X2) as X and all of

,

,

,

,

,

,

, and

have a group represented by (X1) as X.[12] The compound of any one of [6] to [11] above where Yin formulas(G1), (A1), (C1) and (U1) is a methoxy group and Z in formulas (G2),(A2), (C2) and (T2) is an ethylene group, or a pharmacologicallyacceptable salt thereof.[13] A compound represented by the following general formula (I′) or apharmacologically acceptable salt thereof:

(I′) B_(T′1)-B_(M′1)-B_(B′1)where B_(T′1) is a group represented by any one of the following (1a′)to (1o′):

(1a′) HO-, (1b′) HO-Bg-, (1c′) HO-Bc-Bg-, (1d′) HO-Bt-Bc-Bg-, (1e′)HO-Bt-Bt-Bc-Bg-, (1f′) HO-Bc-Bt-Bt-Bc-Bg-, (1g′) HO-Bt-Bc-Bt-Bt-Bc-Bg-,(1h′) HO-Bg-Bt-Bc-Bt-Bt-Bc-Bg-, (1j′) HO-Ba-Bg-Bt-Bc-Bt-Bt-Bc-Bg-, (1k′)HO-Bg-Ba-Bg-Bt-Bc-Bt-Bt-Bc-Bg-, (1l′) (SEQ ID NO: 89)HO-Bt-Bg-Ba-Bg-Bt-Bc-Bt-Bt-Bc-Bg-, (1m′) (SEQ ID NO: 90)HO-Bt-Bt-Bg-Ba-Bg-Bt-Bc-Bt-Bt-Bc-Bg-, (1n′) (SEQ ID NO: 91)HO-Bg-Bt-Bt-Bg-Ba-Bg-Bt-Bc-Bt-Bt-Bc-Bg-, or (1o′) (SEQ ID NO: 2)HO-Ba-Bg-Bt-Bt-Bg-Ba-Bg-Bt-Bc-Bt-Bt-Bc-Bg-,where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M′1) is a group represented by the following formula (1′):

(1′) -Ba-Ba-Ba-Bc-Bt-Bg-Ba-where Bg, Ba, Bt and Bc are as defined above;B_(B′1) is a group represented by any one of the following (12a′) to(12l′):

(12a′)- CH₂CH₂OH, (12b′)- Bg-CH₂CH₂OH, (12c′)- Bg-Bc-CH₂CH₂OH, (12d′)-Bg-Bc-Ba-CH₂CH₂OH, (12e′)- Bg-Bc-Ba-Ba-CH₂CH₂OH, (12f′)-Bg-Bc-Ba-Ba-Ba-CH₂CH₂OH, (12g′)- Bg-Bc-Ba-Ba-Ba-Bt-CH₂CH₂OH, (12h′)-Bg-Bc-Ba-Ba-Ba-Bt-Bt-CH₂CH₂OH, (12i′)- Bg-Bc-Ba-Ba-Ba-Bt-Bt-Bt-CH₂CH₂OH,(12j′)- Bg-Bc-Ba-Ba-Ba-Bt-Bt-Bt-Bg-CH₂CH₂OH, (12k′)- (SEQ ID NO: 92)Bg-Bc-Ba-Ba-Ba-Bt-Bt-Bt-Bg-Bc-CH₂CH₂OH, or (12l′)- (SEQ ID NO: 93)Bg-Bc-Ba-Ba-Ba-Bt-Bt-Bt-Bg-Bc-Bt-CH₂CH₂OH,where Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (I′) has 2′-O,4′-C-alkylene group.[14] A compound represented by the following general formula (II′) or apharmacologically acceptable salt thereof:

(II′) B_(T′2)-B_(M′2)-B_(B′2)where B_(T′2) is a group represented by any one of the following (2a′)to (2j′):

(2a′) HO-, (2b′) HO-Bg-, (2c′) HO-Ba-Bg-, (2d′) HO-Ba-Ba-Bg-, (2e′)HO-Ba-Ba-Ba-Bg-, (2f′) HO-Bc-Ba-Ba-Ba-Bg-, (2g′) HO-Bg-Bc-Ba-Ba-Ba-Bg-,(2h′) HO-Bt-Bg-Bc-Ba-Ba-Ba-Bg-, or (2j′) HO-Bg-Bt-Bg-Bc-Ba-Ba-Ba-Bg-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M′2) is a group represented by the following formula (2′):

(2′) (SEQ ID NO: 94) -Bt-Bt-Bg-Ba-Bg-Bt-Bc-Bt-Bt-Bc-where Bg, Ba, Bt and Bc are as defined above;B_(B′2) is a group represented by any one of the following (22a′) to(22i′):

(22a′)- CH₂CH₂OH, (22b′)- Ba-CH₂CH₂OH, (22c′)- Ba-Ba-CH₂CH₂OH, (22d′)-Ba-Ba-Ba-CH₂CH₂OH, (22e′)- Ba-Ba-Ba-Ba-CH₂CH₂OH, (22f′)-Ba-Ba-Ba-Ba-Bc-CH₂CH₂OH, (22g′)- Ba-Ba-Ba-Ba-Bc-Bt-CH₂CH₂OH, (22h′)-Ba-Ba-Ba-Ba-Bc-Bt-Bg-CH₂CH₂OH, or (22i′)-Ba-Ba-Ba-Ba-Bc-Bt-Bg-Ba-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above; provided that at least oneof the nucleosides constituting the compound represented by formula(II′) has 2′-O,4′-C-alkylene group.[15] A compound represented by the following general formula (III′) or apharmacologically acceptable salt thereof:

(III′) B_(T′3)-B_(M′3)-B_(B′3)where B_(T′3) is a group represented by any one of the following (3a′)to (3c′):

(3a′) HO-, (3b′) HO-Bc-, or (3c′) HO-Bg-Bc-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M′3) is a group represented by the following formula (3′):

(3′) (SEQ ID NO: 95) -Bc-Bg-Bc-Bt-Bg-Bc-Bc-Bc-Ba-Ba-where Bg, Ba, Bt and Bc are as described above)B_(B′3) is a group represented by any one of the following (32a′) to(32i′):

(32a′)- CH₂CH₂OH, (32b′)- Bt-CH₂CH₂OH, (32c′)- Bt-Bg-CH₂CH₂OH, (32d′)-Bt-Bg-Bc-CH₂CH₂OH, (32e′)- Bt-Bg-Bc-Bc-CH₂CH₂OH, (32f′)-Bt-Bg-Bc-Bc-Ba-CH₂CH₂OH, (32g′)- Bt-Bg-Bc-Bc-Ba-Bt-CH₂CH₂OH, (32h′)-Bt-Bg-Bc-Bc-Ba-Bt-Bc-CH₂CH₂OH, or (32i′)-Bt-Bg-Bc-Bc-Ba-Bt-Bc-Bc-CH₂CH₂OH,where Bg, Ba, Bt and Bc are as described above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (III′) has 2′-O,4′-C-alkylene group.[16] A compound represented by the following general formula (IV′) or apharmacologically acceptable salt thereof:

(IV′) B_(T′4)-B_(M′4)-B_(B′4)where B_(T′4) is a group represented by any one of the following (4a′)to (4m′):

(4a′) HO-, (4b′) HO-Ba-, (4c′) HO-Ba-Ba-, (4d′) HO-Bc-Ba-Ba-, (4e′)HO-Ba-Bc-Ba-Ba-, (4f′) HO-Bg-Ba-Bc-Ba-Ba-, (4g′) HO-Bt-Bg-Ba-Bc-Ba-Ba-,(4h′) HO-Bc-Bt-Bg-Ba-Bc-Ba-Ba-, (4j′) HO-Bt-Bc-Bt-Bg-Ba-Bc-Ba-Ba-, (4k′)HO-Bt-Bt-Bc-Bt-Bg-Ba-Bc-Ba-Ba-, (4l′) (SEQ ID NO: 96)HO-Bg-Bt-Bt-Bc-Bt-Bg-Ba-Bc-Ba-Ba-, or (4m′) (SEQ ID NO: 97)HO-Bt-Bg-Bt-Bt-Bc-Bt-Bg-Ba-Bc-Ba-Ba-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M′4) is a group represented by the following formula (4′):

(4′) -Bc-Ba-Bg-Bt-Bt-Bt-Bg-where Bg, Ba, Bt and Bc are as described above;B_(B′4) is a group represented by any one of the following (42a′) to(42l′):

(42a′)- CH₂CH₂OH, (42b′)- Bc-CH₂CH₂OH, (42c′)- Bc-Bc-CH₂CH₂OH, (42d′)-Bc-Bc-Bg-CH₂CH₂OH, (42e′)- Bc-Bc-Bg-Bc-CH₂CH₂OH, (42f′)-Bc-Bc-Bg-Bc-Bt-CH₂CH₂OH, (42g′)- Bc-Bc-Bg-Bc-Bt-Bg-CH₂CH₂OH, (42h′)-Bc-Bc-Bg-Bc-Bt-Bg-Bc-CH₂CH₂OH, (42i′)- Bc-Bc-Bg-Bc-Bt-Bg-Bc-Bc-CH₂CH₂OH,(42j′)- Bc-Bc-Bg-Bc-Bt-Bg-Bc-Bc-Bc-CH₂CH₂OH, (42k′)- (SEQ ID NO: 98)Bc-Bc-Bg-Bc-Bt-Bg-Bc-Bc-Bc-Ba-CH₂CH₂OH, or (42l′)- (SEQ ID NO: 99)Bc-Bc-Bg-Bc-Bt-Bg-Bc-Bc-Bc-Ba-Ba-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as described above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (IV′) has 2′-O,4′-C-alkylene group.[17] A compound represented by the following general formula (V′) or apharmacologically acceptable salt thereof:

(V′) B_(T′5)-B_(M′5)-B_(B′5)where B_(T′5) is a group represented by any one of the following (5a′)to (5g′):

(5a′) HO-, (5b′) HO-Bt-, (5c′) HO-Bt-Bt-, (5d′) HO-Bt-Bt-Bt-, (5e′)HO-Bt-Bt-Bt-Bt-, (5f′) HO-Bc-Bt-Bt-Bt-Bt-, or (5g′)HO-Bg-Bc-Bt-Bt-Bt-Bt-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M′5) is a group represented by the following formula (5′):

(5′) (SEQ ID NO: 100) -Bc-Bt-Bt-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-where Bg, Ba, Bt and Bc are as described above;B_(B′5) is a group represented by any one of the following (52a′) to(52i′):

(52a′)- CH₂CH₂OH, (52b′)- Bt-CH₂CH₂OH, (52c′)- Bt-Bc-CH₂CH₂OH, (52d′)-Bt-Bc-Bt-CH₂CH₂OH, (52e′)- Bt-Bc-Bt-Bt-CH₂CH₂OH, (52f′)-Bt-Bc-Bt-Bt-Bt-CH₂CH₂OH, (52g′)- Bt-Bc-Bt-Bt-Bt-Bt-CH₂CH₂OH, (52h′)-Bt-Bc-Bt-Bt-Bt-Bt-Bc-CH₂CH₂OH, or (52i′)-Bt-Bc-Bt-Bt-Bt-Bt-Bc-Bc-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as described above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (V′) has 2′-O,4′-C-alkylene group.[18] A compound represented by the following general formula (VI′) or apharmacologically acceptable salt thereof:

(VI′) B_(T′6)-B_(M′6)-B_(B′6)where B_(T′6) is a group represented by any one of the following (6a′)to (6r′):

(6a′) HO-, (6b′) HO-Bc-, (6c′) HO-Bt-Bc-, (6d′) HO-Bc-Bt-Bc-, (6e′)HO-Bg-Bc-Bt-Bc-, (6f′) HO-Bt-Bg-Bc-Bt-Bc-, (6g′) HO-Bc-Bt-Bg-Bc-Bt-Bc-,(6h′) HO-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, (6j′) HO-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, (6k′)HO-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, (6l′) (SEQ ID NO: 101)HO-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, (6m′) (SEQ ID NO: 102)HO-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, (6n′) (SEQ ID NO: 103)HO-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, (6o′) (SEQ ID NO: 104)HO-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, (6p′) (SEQ ID NO: 105)HO-Bt-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, (6q′) (SEQ ID NO: 106)HO-Bt-Bt-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-, or (6r′) (SEQ ID NO:107) HO-Bc-Bt-Bt-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt- Bc-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M′6) is a group represented by the following formula (6′):

(6′) -Bt-Bt-Bt-Bt-Bc-Bc-where Bg, Ba, Bt and Bc are as described above;B_(B′6) is a group represented by any one of the following (62a′) to(62m′):

(62a′)- CH₂CH₂OH, (62b′)- Ba-CH₂CH₂OH, (62c′)- Ba-Bg-CH₂CH₂OH, (62d′)-Ba-Bg-Bg-CH₂CH₂OH, (62e′)- Ba-Bg-Bg-Bt-CH₂CH₂OH, (62f′)-Ba-Bg-Bg-Bt-Bt-CH₂CH₂OH, (62g′)- Ba-Bg-Bg-Bt-Bt-Bc-CH₂CH₂OH, (62h′)-Ba-Bg-Bg-Bt-Bt-Bc-Ba-CH₂CH₂OH, (62i′)- Ba-Bg-Bg-Bt-Bt-Bc-Ba-Ba-CH₂CH₂OH,(62j′)- Ba-Bg-Bg-Bt-Bt-Bc-Ba-Ba-Bg-CH₂CH₂OH, (62k′)- (SEQ ID NO: 108)Ba-Bg-Bg-Bt-Bt-Bc-Ba-Ba-Bg-Bt-CH₂CH₂OH, (62l′)- (SEQ ID NO: 109)Ba-Bg-Bg-Bt-Bt-Bc-Ba-Ba-Bg-Bt-Bg-CH₂CH₂OH, or (62m′)- (SEQ ID NO: 110)Ba-Bg-Bg-Bt-Bt-Bc-Ba-Ba-Bg-Bt-Bg-Bg-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as described above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (VI′) has 2′-O,4′-C-alkylene group.[19] A compound represented by the following general formula (VII′) or apharmacologically acceptable salt thereof:

(VII′) B_(T′7)-B_(M′7)-B_(B′7)where B_(T′7) is a group represented by any one of the following (7a′)to (7f′):

(7a′) HO-, (7b′) HO-Bt-, (7c′) HO-Ba-Bt-, (7d′) HO-Bt-Ba-Bt-, (7e′)HO-Bt-Bt-Ba-Bt-, or (7f′) HO-Bg-Bt-Bt-Ba-Bt-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M′7) is a group represented by the following formula (7′):

(7′) (SEQ ID NO: 21) -Bc-Bt-Bg-Bc-Bt-Bt-Bc-Bc-Bt-Bc-Bc-Ba-Ba-Bc-Bc-where Bg, Ba, Bt and Bc are as described above;B_(B′S) is a group represented by the following (72a′):

(72a′)- CH₂CH₂OHprovided that at least one of the nucleosides constituting the compoundrepresented by formula (VII′) has 2′-O,4′-C-alkylene group.[20] The compound of any one of [13] to [19] above which is selectedfrom the group consisting of the following compounds (i′) to (xiii′), ora pharmacologically acceptable salt thereof:(i′) a compound represented by the following formula (i′):

(i′) (SEQ ID NO: 10) HO-Ba-Bg-Bt-Bt-Bg-Ba-Bg-Bt-Bc-Bt-Bt-Bc-Bg-Ba-Ba-Ba-Bc-Bt-Bg-Ba-Bg-Bc-Ba-CH₂CH₂OH(ii′) a compound represented by the following formula (ii′):

(ii′) (SEQ ID NO: 11) HO-Ba-Ba-Ba-Bc-Bt-Bg-Ba-Bg-Bc-Ba-Ba-Ba-Bt-Bt-Bt-Bg-Bc-Bt-CH₂CH₂OH(iii′) a compound represented by the following formula (iii′):

(iii′) (SEQ ID NO: 12) HO-Bt-Bt-Bg-Ba-Bg-Bt-Bc-Bt-Bt-Bc-Ba-Ba-Ba-Ba-Bc-Bt-Bg-Ba-CH₂CH₂OH(iv′) a compound represented by the following formula (iv′):

(iv′) (SEQ ID NO: 13) HO-Bg-Bt-Bg-Bc-Ba-Ba-Ba-Bg-Bt-Bt-Bg-Ba-Bg-Bt-Bc-Bt-Bt-Bc-CH₂CH₂OH(v′) a compound represented by the following formula (v′):

(v′) (SEQ ID NO: 14) HO-Bg-Bc-Bc-Bg-Bc-Bt-Bg-Bc-Bc-Bc-Ba-Ba-Bt-Bg-Bc-CH₂CH₂OH(vi′) a compound represented by the following formula (vi′):

(vi′) (SEQ ID NO: 15) HO-Bc-Bg-Bc-Bt-Bg-Bc-Bc-Bc-Ba-Ba-Bt-Bg-Bc-Bc-Ba-Bt-Bc-Bc-CH₂CH₂OH(vii′) a compound represented by the following formula (vii′):

(vii′) (SEQ ID NO: 16) HO-Bc-Ba-Bg-Bt-Bt-Bt-Bg-Bc-Bc-Bg-Bc-Bt-Bg-Bc-Bc-Bc-Ba-Ba-CH₂CH₂OH(viii′) a compound represented by the following formula (viii′):

(viii′) (SEQ ID NO: 17) HO-Bt-Bg-Bt-Bt-Bc-Bt-Bg-Ba-Bc-Ba-Ba-Bc-Ba-Bg-Bt-Bt-Bt-Bg-CH₂CH₂OH(ix′) a compound represented by the following formula (ix′):

(ix′) (SEQ ID NO: 18) HO-Bg-Bc-Bt-Bt-Bt-Bt-Bc-Bt-Bt-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-CH₂CH₂OH(x′) a compound represented by the following formula (x′):

(x′) (SEQ ID NO: 19) HO-Bc-Bt-Bt-Bt-Bt-Ba-Bg-Bt-Bt-Bg-Bc-Bt-Bg-Bc-Bt-Bc-Bt-Bt-Bt-Bt-Bc-Bc-CH₂CH₂OH(xi′) a compound represented by the following formula (xi′):

(xi′) (SEQ ID NO: 20) HO-Bt-Bt-Bt-Bt-Bc-Bc-Ba-Bg-Bg-Bt-Bt-Bc-Ba-Ba-Bg-Bt-Bg-Bg-CH₂CH₂OH(xii′) a compound represented by the following formula (xii′):

(xii′) (SEQ ID NO: 21) HO-Bc-Bt-Bg-Bc-Bt-Bt-Bc-Bc-Bt-Bc-Bc-Ba-Ba-Bc-Bc-CH₂CH₂OH(xiii′) a compound represented by the following formula (xiii′):

(xiii′) (SEQ ID NO: 22) HO-Bg-Bt-Bt-Ba-Bt-Bc-Bt-Bg-Bc-Bt-Bt-Bc-Bc-Bt-Bc-Bc-Ba-Ba-Bc-Bc-CH₂CH₂OHwhere Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms.[21] The compound of any one of [13] to [20] above which is representedby any one of the following compounds (I′1) to (I′20), or apharmacologically acceptable salt thereof:

(I′1) (SEQ ID NO: 10) HO-Ba**-Bg**-Bt**-Bt**-Bg**-Ba*-Bg*-Bt*-Bc*-Bt*-Bt*-Bc*-Bg*-Ba*-Ba*-Ba*-Bc*-Bt*-Bg**-Ba**-Bg**- Bc**-Ba**-CH₂CH₂OH (I′2)(SEQ ID NO: 10) HO-Ba**-Bg**-Bt**-Bt**-Bg**-Ba**-Bg**-Bt**-Bc*-Bt*-Bt*-Bc*-Bg*-Ba*-Ba*-Ba**-Bc**-Bt**-Bg**-Ba**-Bg**-Bc**-Ba**-CH₂CH₂OH (I′3) (SEQ ID NO: 11)HO-Ba**-Ba**-Ba**-Bc**-Bt**-Bg*-Ba*-Bg*-Bc*-Ba*-Ba*-Ba*-Bt*-Bt**-Bt**-Bg**-Bc**-Bt**-CH₂CH₂OH (I′4) (SEQ ID NO: 12)HO-Bt**-Bt**-Bg**-Ba**-Bg**-Bt*-Bc*-Bt*-Bt*-Bc*-Ba*-Ba*-Ba*-Ba**-Bc**-Bt**-Bg**-Ba**-CH₂CH₂OH (I′5) (SEQ ID NO: 13)HO-Bg**-Bt**-Bg**-Bc**-Ba**-Ba*-Ba*-Bg*-Bt*-Bt*-Bg*-Ba*-Bg*-Bt**-Bc**-Bt**-Bt**-Bc**-CH₂CH₂OH (I′6) (SEQ ID NO: 12)HO-Bt**-Bt**-Bg*-Ba*-Bg*-Bt**-Bc**-Bt**-Bt**-Bc**-Ba*-Ba*-Ba*-Ba*-Bc**-Bt**-Bg*-Ba*-CH₂CH₂OH (I′7) (SEQ ID NO: 13)HO-Bg*-Bt**-Bg*-Bc**-Ba*-Ba*-Ba*-Bg*-Bt**-Bt**-Bg*-Ba*-Bg*-Bt**-Bc**-Bt**-Bt**-Bc**-CH₂CH₂OH (I′8) (SEQ ID NO: 14)HO-Bg**-Bc**-Bc**-Bg**-Bc**-Bt*-Bg*-Bc*-Bc*-Bc*-Ba**-Ba**-Bt**-Bg**-Bc**-CH₂CH₂OH (I′9) (SEQ ID NO: 15)HO-Bc**-Bg*-Bc**-Bt**-Bg*-Bc*-Bc**-Bc**-Ba*-Ba*-Bt**-Bg*-Bc**-Bc**-Ba*-Bt*-Bc**-Bc**-CH₂CH₂OH (I′10) (SEQ ID NO: 16)HO-Bc**-Ba*-Bg*-Bt**-Bt**-Bt*-Bg*-Bc**-Bc**-Bg*-Bc**-Bt**-Bg*-Bc**-Bc**-Bc**-Ba*-Ba*-CH₂CH₂OH (I′11) (SEQ ID NO: 17)HO-Bt**-Bg*-Bt**-Bt**-Bc**-Bt**-Bg*-Ba*-Bc**-Ba*-Ba*-Bc**-Ba*-Bg*-Bt**-Bt**-Bt**-Bg*-CH₂CH₂OH (I′12) (SEQ ID NO: 15)HO-Bc**-Bg*-Bc**-Bt**-Bg*-Bc*-Bc**-Bc**-Ba*-Ba*-Bt**-Bg*-Bc**-Bc**-Ba*-Bt*-Bc**-Bc**- CH₂CH₂OH (I′13) (SEQ ID NO: 18)HO-Bg**-Bc**-Bt**-Bt**-Bt**-Bt*-Bc*-Bt*-Bt*-Bt*-Bt*-Ba*-Bg*-Bt*-Bt*-Bg**-Bc**-Bt**-Bg**-Bc**- CH₂CH₂OH (I′14) (SEQ IDNO: 19) HO-Bc*-Bt*-Bt*-Bt*-Bt*-Ba**-Bg**-Bt**-Bt**-Bg**-Bc**-Bt**-Bg**-Bc**-Bt**-Bc**-Bt**-Bt*-Bt*-Bt*- Bc*-Bc*-CH₂CH₂OH (I′15)(SEQ ID NO: 21) HO-Bc**-Bt**-Bg**-Bc**-Bt**-Bt*-Bc*-Bc*-Bt*-Bc*-Bc**-Ba**-Ba**-Bc**-Bc**-CH₂CH₂OH (I′16) (SEQ ID NO: 22)HO-Bg**-Bt**-Bt**-Ba**-Bt**-Bc*-Bt*-Bg*-Bc*-Bt*-Bt*-Bc*-Bc*-Bt*-Bc*-Bc**-Ba**-Ba**-Bc**-Bc**- CH₂CH₂OH (I′17) (SEQ IDNO: 19) HO-Bc**-Bt**-Bt**-Bt**-Bt**-Ba*-Bg*-Bt*-Bt*-Bg*-Bc*-Bt*-Bg*-Bc*-Bt*-Bc*-Bt*-Bt**-Bt**-Bt**-Bc**- Bc**-CH₂CH₂OH (I′18)(SEQ ID NO: 20) HO-Bt**-Bt**-Bt**-Bt**-Bc**-Bc*-Ba*-Bg*-Bg*-Bt*-Bt*-Bc*-Ba*-Ba**-Bg**-Bt**-Bg**-Bg**-CH₂CH₂OH (I′19) (SEQ ID NO: 21)HO-Bc**-Bt*-Bg*-Bc**-Bt*-Bt*-Bc**-Bc**-Bt*-Bc**-Bc**-Ba*-Ba*-Bc**-Bc**-CH₂CH₂OH (I′20) (SEQ ID NO: 21)HO-Bc**-Bt**-Bg*-Bc**-Bt**-Bt*-Bc*-Bc**-Bt*-Bc*-Bc**-Ba*-Ba*-Bc**-Bc**-CH₂CH₂OHwhere Bg* is a group represented by the following formula (G1^(a)); Ba*is a group represented by the following formula (A1^(a)); Bc* is a grouprepresented by the following formula (C1^(a)); Bt* is a grouprepresented by the following formula (U1^(a)); Bg** is a grouprepresented by the following formula (G2); Ba** is a group representedby the following formula (A2); Bc** is a group represented by thefollowing formula (C2); and Bt** is a group represented by the followingformula (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2); R¹ is individually and independently analkyl group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms:

[22] The compound of [21] above where X in formulas (G1^(a)), (A1^(a)),(C1^(a)) and (U1^(a)) is a group represented by formula (X2) and X informulas (G2), (A2), (C2) and (T2) is a group represented by formula(X1), or a pharmacologically acceptable salt thereof.[23] The compound of [21] above where X in all the formulas (G1^(a)),(A1^(a)), (C1^(a)), (U1^(a)), (G2), (A2), (C2) and (T2) is a grouprepresented by formula (X2), or a pharmacologically acceptable saltthereof.[24] The compound of [21] above which is represented by any one of thefollowing formulas (I′1-a) to (I′20-b), or a pharmacologicallyacceptable salt thereof:

(I′1-a) (SEQ ID NO: 10)

(I′2-a) (SEQ ID NO: 10)

(I′3-a) (SEQ ID NO: 11)

(I′4-a) (SEQ ID NO: 12)

(I′5-a) (SEQ ID NO: 13)

(I′6-a) (SEQ ID NO: 12)

(I′6-b) (SEQ ID NO: 12)

(I′6-c) (SEQ ID NO: 12) HO-Bt**-Bt**-Bg*-Ba*-Bg*-Bt**-Bc**-Bt**-Bt**-Bc**-Ba*-Ba*-Ba*-Ba*-Bc**-Bt**-Bg*- Ba*-CH₂CH₂OH (I′7-a)(SEQ ID NO: 13)

(I′7-b) (SEQ ID NO: 13)

(I′7-c) (SEQ ID NO: 13) HO-Bg*-Bt**-Bg*-Bc**-Ba*-Ba*-Ba*-Bg*-Bt**-Bt**-Bg*-Ba*-Bg*-Bt**-Bc**-Bt**-Bt**- Bc**-CH₂CH₂OH (I′8-a)(SEQ ID NO: 14)

(I′9-a) (SEQ ID NO: 15)

(I′10-a) (SEQ ID NO: 16)

(I′11-a) (SEQ ID NO: 17)

(I′12-a) (SEQ ID NO: 15) HO-Bc**-Bg*-Bc**-Bt**-Bg*-Bc*-Bc**-Bc**-Ba*-Ba*-Bt**-Bg*-Bc**-Bc**-Ba*-Bt*-Bc**- Bc**-CH₂CH₂OH (I′13-a)(SEQ ID NO: 18)

(I′14-a) (SEQ ID NO: 19)

(I′15-a) (SEQ ID NO: 21)

(I′16-a) (SEQ ID NO: 22)

(I′17-a) (SEQ ID NO: 19)

(I′18-a) (SEQ ID NO: 20)

(I′18-b) (SEQ ID NO: 21) HO-Bc**-Bt**-Bg**-Bc**-Bt**-Bt*-Bc*-Bc*-Bt*-Bc*-Bc**-Ba**-Ba**-Bc**-Bc**-CH₂CH₂OH (I′19-a) (SEQ ID NO: 21)

(I′19-b) (SEQ ID NO: 21) HO-Bc**-Bt*-Bg*-Bc**-Bt*-Bt*-Bc**-Bc**-Bt*-Bc**-Bc**-Ba*-Ba*-Bc**-Bc**-CH₂CH₂OH (I′20-a) (SEQ ID NO: 21)

(I′20-b) (SEQ ID NO: 21) HO-Bc**-Bt**-Bg*-Bc**-Bt**-Bt*-Bc*-Bc**-Bt*-Bc*-Bc**-Ba*-Ba*-Bc**-Bc**-CH₂CH₂OHwhere Bg* is a group represented by formula (G1^(a)), Ba* is a grouprepresented by formula (A1^(a)); Bc* is a group represented by formula(C1^(a)); Bt* is a group represented by formula (U1^(a)); Bg** is agroup represented by formula (G2); Ba** is a group represented byformula (A2); Bc** is a group represented by formula (C2); Bt** is agroup represented by formula (T2); and in individual formulas, at leastone of Bg*, Ba*, Bc*, Bt*, Bg**, Ba**, Bc** and Bt** has a grouprepresented by formula (X2) as X and all of

,

,

,

,

,

,

and

have a group represented by (X1) as X.[25] The compound of any one of [13] to [24] above where Y in formulas(G1), (A1), (C1) and (U1) is a methoxy group and Z in formulas (G2),(A2), (C2) and (T2) is an ethylene group, or a pharmacologicallyacceptable salt thereof.[26] A compound represented by the following general formula (I″) or apharmacologically acceptable salt thereof:

(I″) B_(T″1)-B_(M″1)-B_(B″1)where B_(T″1) is a group represented by any one of the following (1a″)to (1m″):

(1a″) HO-, (1b″) HO-Bt-, (1c″) HO-Bt-Bt-, (1d″) HO-Bt-Bt-Bt-, (1e″)HO-Ba-Bt-Bt-Bt-, (1f″) HO-Bt-Ba-Bt-Bt-Bt-, (1g″) HO-Bg-Bt-Ba-Bt-Bt-Bt-,(1h″) HO-Bt-Bg-Bt-Ba-Bt-Bt-Bt-, (1i″) HO-Bt-Bt-Bg-Bt-Ba-Bt-Bt-Bt-, (1j″)HO-Bt-Bt-Bt-Bg-Bt-Ba-Bt-Bt-Bt-, (1k″) (SEQ ID NO: 111)HO-Ba-Bt-Bt-Bt-Bg-Bt-Ba-Bt-Bt-Bt-, (1l″) (SEQ ID NO: 112)HO-Bc-Ba-Bt-Bt-Bt-Bg-Bt-Ba-Bt-Bt-Bt-, or (1m″) (SEQ ID NO: 113)HO-Bc-Bc-Ba-Bt-Bt-Bt-Bg-Bt-Ba-Bt-Bt-Bt-,where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″1) is a group represented by the following formula (1″):

(1″) -Ba-Bg-Bc-Ba-Bt-Bg-where Bg, Ba, Bt and Bc are as defined above;B_(B″1) is a group represented by any one of the following (101a″) to(101m″):

(101a″)- CH₂CH₂OH, (101b″)- Bt-CH₂CH₂OH, (101c″)- Bt-Bt-CH₂CH₂OH,(101d″)- Bt-Bt-Bc-CH₂CH₂OH, (101e″)- Bt-Bt-Bc-Bc-CH₂CH₂OH, (101f″)-Bt-Bt-Bc-Bc-Bc-CH₂CH₂OH, (101g″)- Bt-Bt-Bc-Bc-Bc-Ba-CH₂CH₂OH, (101h″)-Bt-Bt-Bc-Bc-Bc-Ba-Ba-CH₂CH₂OH, (101i″)-Bt-Bt-Bc-Bc-Bc-Ba-Ba-Bt-CH₂CH₂OH, (101j″)-Bt-Bt-Bc-Bc-Bc-Ba-Ba-Bt-Bt-CH₂CH₂OH, (101k″)- (SEQ ID NO: 114)Bt-Bt-Bc-Bc-Bc-Ba-Ba-Bt-Bt-Bc-CH₂CH₂OH, (101l″)- (SEQ ID NO: 115)Bt-Bt-Bc-Bc-Bc-Ba-Ba-Bt-Bt-Bc-Bt-CH₂CH₂OH, or (101m″)- (SEQ ID NO: 116)Bt-Bt-Bc-Bc-Bc-Ba-Ba-Bt-Bt-Bc-Bt-Bc-CH₂CH₂OH,where Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (I″) has 2″-O,4″-C-alkylene group.[27] A compound represented by the following general formula (II″) or apharmacologically acceptable salt thereof:

(II″) B_(T″2)-B_(M″2)-B_(B″2)where B_(T″2) is a group represented by any one of the following (2a″)to (2g″):

(2a″) HO-, (2b″) HO-Bg-, (2c″) HO-Bt-Bg-, (2d″) HO-Ba-Bt-Bg-, (2e″)HO-Bc-Ba-Bt-Bg-, (2f″) HO-Bg-Bc-Ba-Bt-Bg-, or (2g″)HO-Ba-Bg-Bc-Ba-Bt-Bg-,where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″2) is a group represented by the following formula (2″):

(2″) (SEQ ID NO: 116) -Bt-Bt-Bc-Bc-Bc-Ba-Ba-Bt-Bt-Bc-Bt-Bc-where Bg, Ba, Bt and Bc are as defined above;B_(B″2) is a group represented by any one of the following (102a″) to(102g″):

(102a″)- CH₂CH₂OH, (102b″)- Ba-CH₂CH₂OH, (102c″)- Ba-Bg-CH₂CH₂OH,(102d″)- Ba-Bg-Bg-CH₂CH₂OH, (102e″)- Ba-Bg-Bg-Ba-CH₂CH₂OH, (102f″)-Ba-Bg-Bg-Ba-Ba-CH₂CH₂OH, or (102g″)- Ba-Bg-Bg-Ba-Ba-Bt-CH₂CH₂OH,where Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (II″) has 2″-O,4″-C-alkylene group.[28] A compound represented by the following general formula (III″) or apharmacologically acceptable salt thereof:

(III″) B_(T″3)-B_(M″3)-B_(B″3)where B_(T″3) is a group represented by any one of the following (3a″)to (3m″):

(3a″) HO-, (3b″) HO-Bc-, (3c″) HO-Ba-Bc-, (3d″) HO-Ba-Ba-Bc-, (3e″)HO-Ba-Ba-Ba-Bc-, (3f″) HO-Ba-Ba-Ba-Ba-Bc-, (3g″) HO-Bg-Ba-Ba-Ba-Ba-Bc-,(3h″) HO-Bt-Bg-Ba-Ba-Ba-Ba-Bc-, (3i″) HO-Ba-Bt-Bg-Ba-Ba-Ba-Ba-Bc-, (3j″)HO-Ba-Ba-Bt-Bg-Ba-Ba-Ba-Ba-Bc-, (3k″) (SEQ ID NO: 117)HO-Bt-Ba-Ba-Bt-Bg-Ba-Ba-Ba-Ba-Bc-, (3l″) (SEQ ID NO: 118)HO-Ba-Bt-Ba-Ba-Bt-Bg-Ba-Ba-Ba-Ba-Bc-, or (3m″) (SEQ ID NO: 119)HO-Bc-Ba-Bt-Ba-Ba-Bt-Bg-Ba-Ba-Ba-Ba-Bc-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″3) is a group represented by the following formula (3″):

(3″) -Bg-Bc-Bc-Bg-Bc-Bc-where Bg, Ba, Bt and Bc are as defined above;B_(B″3) is a group represented by any one of the following (103a″) to(103m″):

(103a″)- CH₂CH₂OH, (103b″)- Ba-CH₂CH₂OH, (103c″)- Ba-Bt-CH₂CH₂OH,(103d″)- Ba-Bt-Bt-CH₂CH₂OH, (103e″)- Ba-Bt-Bt-Bt-CH₂CH₂OH, (103f″)-Ba-Bt-Bt-Bt-Bc-CH₂CH₂OH, (103g″)- Ba-Bt-Bt-Bt-Bc-Bt-CH₂CH₂OH, (103h″)-Ba-Bt-Bt-Bt-Bc-Bt-Bc-CH₂CH₂OH, (103i″)-Ba-Bt-Bt-Bt-Bc-Bt-Bc-Ba-CH₂CH₂OH, (103j″)-Ba-Bt-Bt-Bt-Bc-Bt-Bc-Ba-Ba-CH₂CH₂OH, (103k″)- (SEQ ID NO: 120)Ba-Bt-Bt-Bt-Bc-Bt-Bc-Ba-Ba-Bc-CH₂CH₂OH, (103l″)- (SEQ ID NO: 121)Ba-Bt-Bt-Bt-Bc-Bt-Bc-Ba-Ba-Bc-Ba-CH₂CH₂OH, or (103m″)- (SEQ ID NO: 122)Ba-Bt-Bt-Bt-Bc-Bt-Bc-Ba-Ba-Bc-Ba-Bg-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (III″) has 2″-O,4″-C-alkylene group.[29] A compound represented by the following general formula (IV″) or apharmacologically acceptable salt thereof:

(IV″) B_(T″4)-B_(M″4)-B_(B″4)where B_(T″4) is a group represented by any one of the following (4a″)to (4j″):

(4a″) HO-, (4b″) HO-Ba-, (4c″) HO-Bc-Ba-, (4d″) HO-Bt-Bc-Ba-, (4e″)HO-Bg-Bt-Bc-Ba-, (4f″) HO-Bg-Bg-Bt-Bc-Ba-, (4g″) HO-Ba-Bg-Bg-Bt-Bc-Ba-,(4h″) HO-Bt-Ba-Bg-Bg-Bt-Bc-Ba-, (4i″) HO-Bc-Bt-Ba-Bg-Bg-Bt-Bc-Ba-, or(4j″) HO-Bg-Bc-Bt-Ba-Bg-Bg-Bt-Bc-Ba-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″4) is a group represented by the following formula (4″):

(4″) -Bg-Bg-Bc-Bt-Bg-Bc-Bt-Bt-Bt-where Bg, Ba, Bt and Bc are as defined above;B_(B″4) is a group represented by any one of the following (104a″) to(104j″):

(104a″)- CH₂CH₂OH, (104b″)- Bg-CH₂CH₂OH, (104c″)- Bg-Bc-CH₂CH₂OH,(104d″)- Bg-Bc-Bc-CH₂CH₂OH, (104e″)- Bg-Bc-Bc-Bc-CH₂CH₂OH, (104f″)-Bg-Bc-Bc-Bc-Bt-CH₂CH₂OH, (104g″)- Bg-Bc-Bc-Bc-Bt-Bc-CH₂CH₂OH, (104h″)-Bg-Bc-Bc-Bc-Bt-Bc-Ba-CH₂CH₂OH, (104i″)-Bg-Bc-Bc-Bc-Bt-Bc-Ba-Bg-CH₂CH₂OH, or (104j″)-Bg-Bc-Bc-Bc-Bt-Bc-Ba-Bg-Bc-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (IV″) has 2″-O,4″-C-alkylene group.[30] A compound represented by the following general formula (V″) or apharmacologically acceptable salt thereof:

(V″) B_(T″5)-B_(M″5)-B_(B″5)where B_(T″5) is a group represented by any one of the following (5a″)to (5j″):

(5a″) HO-, (5b″) HO-Ba-, (5c″) HO-Bg-Ba-, (5d″) HO-Bg-Bg-Ba-, (5e″)HO-Ba-Bg-Bg-Ba-, (5f″) HO-Bc-Ba-Bg-Bg-Ba-, (5g″) HO-Bc-Bc-Ba-Bg-Bg-Ba-,(5h″) HO-Bt-Bc-Bc-Ba-Bg-Bg-Ba-, (5i″) HO-Bg-Bt-Bc-Bc-Ba-Bg-Bg-Ba-, or(5j″) HO-Ba-Bg-Bt-Bc-Bc-Ba-Bg-Bg-Ba-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″5) is a group represented by the following formula (5″):

(5″) -Bg-Bc-Bt-Ba-Bg-Bg-Bt-Bc-Ba-where Bg, Ba, Bt and Bc are as defined above;B_(B″5) is a group represented by any one of the following (105a″) to(105j″):

(105a″)- CH₂CH₂OH, (105b″)- Bg-CH₂CH₂OH, (105c″)- Bg-Bg-CH₂CH₂OH,(105d″)- Bg-Bg-Bc-CH₂CH₂OH, (105e″)- Bg-Bg-Bc-Bt-CH₂CH₂OH, (105f″)-Bg-Bg-Bc-Bt-Bg-CH₂CH₂OH, (105g″)- Bg-Bg-Bc-Bt-Bg-Bc-CH₂CH₂OH, (105h″)-Bg-Bg-Bc-Bt-Bg-Bc-Bt-CH₂CH₂OH, (105i″)-Bg-Bg-Bc-Bt-Bg-Bc-Bt-Bt-CH₂CH₂OH, or (105j″)-Bg-Bg-Bc-Bt-Bg-Bc-Bt-Bt-Bt-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (V″) has 2″-O,4″-C-alkylene group.[31] A compound represented by the following general formula (VI″) or apharmacologically acceptable salt thereof:

(VI″) B_(T″6)-B_(M″6)-B_(B″6)where B_(T″6) is a group represented by any one of the following (6a″)to (6j″):

(6a″) HO-, (6b″) HO-Ba-, (6c″) HO-Ba-Ba-, (6d″) HO-Ba-Ba-Ba-, (6e″)HO-Bc-Ba-Ba-Ba-, (6f″) HO-Bc-Bc-Ba-Ba-Ba-, (6g″) HO-Bt-Bc-Bc-Ba-Ba-Ba-,(6h″) HO-Bt-Bt-Bc-Bc-Ba-Ba-Ba-, (6i″) HO-Bc-Bt-Bt-Bc-Bc-Ba-Ba-Ba-, or(6j″) HO-Bt-Bc-Bt-Bt-Bc-Bc-Ba-Ba-Ba-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″6) is a group represented by the following formula (6″):

(6″) -Bg-Bc-Ba-Bg-Bc-Bc-Bt-Bc-Bt-where Bg, Ba, Bt and Bc are as defined above;B_(B″6) is a group represented by any one of the following (106a″) to(106j″):

(106a″)- CH₂CH₂OH, (106b″)- Bc-CH₂CH₂OH, (106c″)- Bc-Bg-CH₂CH₂OH,(106d″)- Bc-Bg-Bc-CH₂CH₂OH, (106e″)- Bc-Bg-Bc-Bt-CH₂CH₂OH, (106f″)-Bc-Bg-Bc-Bt-Bc-CH₂CH₂OH, (106g″)- Bc-Bg-Bc-Bt-Bc-Ba-CH₂CH₂OH, (106h″)-Bc-Bg-Bc-Bt-Bc-Ba-Bc-CH₂CH₂OH, (106i″)-Bc-Bg-Bc-Bt-Bc-Ba-Bc-Bt-CH₂CH₂OH, or (106j″)-Bc-Bg-Bc-Bt-Bc-Ba-Bc-Bt-Bc-CH₂CH₂OH,where Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (VI″) has 2″-O,4″-C-alkylene group.[32] A compound represented by the following general formula (VII″) or apharmacologically acceptable salt thereof:

(VII″) B_(T″7)-B_(M″7)-B_(B″7)where B_(T″7) is a group represented by any one of the following (7a″)to (7j″):

(7a″) HO-, (7b″) HO-Bt-, (7c″) HO-Bt-Bt-, (7d″) HO-Bg-Bt-Bt-, (7e″)HO-Ba-Bg-Bt-Bt-, (7f″) HO-Bg-Ba-Bg-Bt-Bt-, (7g″) HO-Bt-Bg-Ba-Bg-Bt-Bt-,(7h″) HO-Ba-Bt-Bg-Ba-Bg-Bt-Bt-, (7i″) HO-Bt-Ba-Bt-Bg-Ba-Bg-Bt-Bt-, or(7j″) HO-Bc-Bt-Ba-Bt-Bg-Ba-Bg-Bt-Bt-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″7) is a group represented by the following formula (7″):

(7″) -Bt-Bc-Bt-Bt-Bc-Bc-Ba-Ba-Ba-where Bg, Ba, Bt and Bc are as defined above;B_(B″7) is a group represented by any one of the following (107a″) to(107j″):

(107a″)- CH₂CH₂OH, (107b″)- Bg-CH₂CH₂OH, (107c″)- Bg-Bc-CH₂CH₂OH,(107d″)- Bg-Bc-Ba-CH₂CH₂OH, (107e″)- Bg-Bc-Ba-Bg-CH₂CH₂OH, (107f″)-Bg-Bc-Ba-Bg-Bc-CH₂CH₂OH, (107g″)- Bg-Bc-Ba-Bg-Bc-Bc-CH₂CH₂OH, (107h″)-Bg-Bc-Ba-Bg-Bc-Bc-Bt-CH₂CH₂OH, (107i″)-Bg-Bc-Ba-Bg-Bc-Bc-Bt-Bc-CH₂CH₂OH, or (107j″)-Bg-Bc-Ba-Bg-Bc-Bc-Bt-Bc-Bt-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (VII″) has 2″-O,4″-C-alkylene group.[33] A compound represented by the following general formula (VIII″) ora pharmacologically acceptable salt thereof:

(VIII″) B_(T″8)-B_(M″8)-B_(B″8)where B_(T″8) is a group represented by any one of the following (8a″)to (8n″):

(8a″) HO-, (8b″) HO-Bc-, (8c″) HO-Bt-Bc-, (8d″) HO-Ba-Bt-Bc-, (8e″)HO-Bc-Ba-Bt-Bc-, (8f″) HO-Bt-Bc-Ba-Bt-Bc-, (8g″) HO-Bt-Bt-Bc-Ba-Bt-Bc-,(8h″) HO-Bt-Bt-Bt-Bc-Ba-Bt-Bc-, (8i″) HO-Bg-Bt-Bt-Bt-Bc-Ba-Bt-Bc-, (8j″)HO-Bt-Bg-Bt-Bt-Bt-Bc-Ba-Bt-Bc-, (8k″) (SEQ ID NO: 123)HO-Bt-Bt-Bg-Bt-Bt-Bt-Bc-Ba-Bt-Bc-, (8l″) (SEQ ID NO: 124)HO-Ba-Bt-Bt-Bg-Bt-Bt-Bt-Bc-Ba-Bt-Bc-, (8m″) (SEQ ID NO: 125)HO-Bc-Ba-Bt-Bt-Bg-Bt-Bt-Bt-Bc-Ba-Bt-Bc-, or (8n″) (SEQ ID NO: 126)HO-Bc-Bc-Ba-Bt-Bt-Bg-Bt-Bt-Bt-Bc-Ba-Bt-Bc-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″8) is a group represented by the following formula (8″):

(8″) -Ba-Bg-Bc-Bt-Bc-where Bg, Ba, Bt and Bc are as defined above;B_(B″8) is a group represented by any one of the following (108a″) to(108n″):

(108a″)- CH₂CH₂OH, (108b″)- Bt-CH₂CH₂OH, (108c″)- Bt-Bt-CH₂CH₂OH,(108d″)- Bt-Bt-Bt-CH₂CH₂OH, (108e″)- Bt-Bt-Bt-Bt-CH₂CH₂OH, (108f″)-Bt-Bt-Bt-Bt-Ba-CH₂CH₂OH, (108g″)- Bt-Bt-Bt-Bt-Ba-Bc-CH₂CH₂OH, (108h″)-Bt-Bt-Bt-Bt-Ba-Bc-Bt-CH₂CH₂OH, (108i″)-Bt-Bt-Bt-Bt-Ba-Bc-Bt-Bc-CH₂CH₂OH, (108j″)-Bt-Bt-Bt-Bt-Ba-Bc-Bt-Bc-Bc-CH₂CH₂OH, (108k″)- (SEQ ID NO: 127)Bt-Bt-Bt-Bt-Ba-Bc-Bt-Bc-Bc-Bc-CH₂CH₂OH, (108l″)- (SEQ ID NO: 128)Bt-Bt-Bt-Bt-Ba-Bc-Bt-Bc-Bc-Bc-Bt-CH₂CH₂OH, (108m″)- (SEQ ID NO: 129)Bt-Bt-Bt-Bt-Ba-Bc-Bt-Bc-Bc-Bc-Bt-Bt-CH₂CH₂OH, or (108n″)- (SEQ ID NO:130) Bt-Bt-Bt-Bt-Ba-Bc-Bt-Bc-Bc-Bc-Bt-Bt-Bg-CH₂CH₂OH,where Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (VIII″) has 2″-O,4″-C-alkylene group.[34] A compound represented by the following general formula (IX″) or apharmacologically acceptable salt thereof:

(IX″) B_(T″9)-B_(M″9)-B_(B″9)where B_(T″9) is a group represented by any one of the following (9a″)to (9n″):

(9a″) D-, (9b″) D-Bg-, (9c″) D-Ba-Bg-, (9d″) D-Bg-Ba-Bg-, (9e″)D-Ba-Bg-Ba-Bg-, (9f″) D-Bc-Ba-Bg-Ba-Bg-, (9g″) D-Bc-Bc-Ba-Bg-Ba-Bg-,(9h″) D-Ba-Bc-Bc-Ba-Bg-Ba-Bg-, (9i″) D-Bc-Ba-Bc-Bc-Ba-Bg-Ba-Bg-, (9j″)D-Bt-Bc-Ba-Bc-Bc-Ba-Bg-Ba-Bg-, (9k″) (SEQ ID NO: 131)D-Bg-Bt-Bc-Ba-Bc-Bc-Ba-Bg-Ba-Bg-, (9l″) (SEQ ID NO: 132)D-Bt-Bg-Bt-Bc-Ba-Bc-Bc-Ba-Bg-Ba-Bg-, (9m″) (SEQ ID NO: 133)D-Bg-Bt-Bg-Bt-Bc-Ba-Bc-Bc-Ba-Bg-Ba-Bg-, or (9n″) (SEQ ID NO: 134)D-Bt-Bg-Bt-Bg-Bt-Bc-Ba-Bc-Bc-Ba-Bg-Ba-Bg-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); Bt is a grouprepresented by the following formula (U1) or (T2); and D is HO— or Ph-wherein Ph- is a group represented by the following first formula:

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″9) is a group represented by the following formula (9″):

(9″)- Bt-Ba-Ba-Bc-Ba-Bg-Bt-where Bg, Ba, Bt and Bc are as defined above;B_(B″9) is a group represented by any one of the following (109a″) to(1091″):

(109a″)- CH₂CH₂OH, (109b″)- Bc-CH₂CH₂OH, (109c″)- Bc-Bt-CH₂CH₂OH,(109d″)- Bc-Bt-Bg-CH₂CH₂OH, (109e″)- Bc-Bt-Bg-Ba-CH₂CH₂OH, (109f″)-Bc-Bt-Bg-Ba-Bg-CH₂CH₂OH, (109g″)- Bc-Bt-Bg-Ba-Bg-Bt-CH₂CH₂OH, (109h″)-Bc-Bt-Bg-Ba-Bg-Bt-Ba-CH₂CH₂OH, (109i″)-Bc-Bt-Bg-Ba-Bg-Bt-Ba-Bg-CH₂CH₂OH, (109j″)-Bc-Bt-Bg-Ba-Bg-Bt-Ba-Bg-Bg-CH₂CH₂OH, (109k″)- (SEQ ID NO: 135)Bc-Bt-Bg-Ba-Bg-Bt-Ba-Bg-Bg-Ba-CH₂CH₂OH, or (109l″)- (SEQ ID NO: 136)Bc-Bt-Bg-Ba-Bg-Bt-Ba-Bg-Bg-Ba-Bg-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (IX″) has 2″-O,4″-C-alkylene group.[35] A compound represented by the following general formula (X″) or apharmacologically acceptable salt thereof:

(X″) B_(T″10)-B_(M″10)-B_(B″10)where B_(T″10) is a group represented by any one of the following (10a″)to (10e″):

(10a″) D-, (10b″) D-Bt-, (10c″) D-Bg-Bt-, (10d″) D-Bg-Bg-Bt-, or (10e″)D-Ba-Bg-Bg-Bt-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); Bt is a grouprepresented by the following formula (U1) or (T2); and D is HO— or Ph-wherein Ph- is a group represented by the following first formula:

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″10) is a group represented by the following formula (10″):

(10″) (SEQ ID NO: 137) -Bt-Bg-Bt-Bg-Bt-Bc-Ba-Bc-Bc-Ba-Bg-Ba-Bg-Bt-Ba-Ba-where Bg, Ba, Bt and Bc are as defined above;B_(B″10) is a group represented by any one of the following (110a″) to(110e″):

(110a″)- CH₂CH₂OH, (110b″)- Bc-CH₂CH₂OH, (110c″)- Bc-Ba-CH₂CH₂OH,(110d″)- Bc-Ba-Bg-CH₂CH₂OH, or (110e″)- Bc-Ba-Bg-Bt-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (X″) has 2″-O,4″-C-alkylene group.[36] A compound represented by the following general formula (XI″) or apharmacologically acceptable salt thereof:

(XI″) B_(T″11)-B_(M″11)-B_(B″11)where B_(T″11) is a group represented by any one of the following (11a″)to (11j″):

(11a″) D-, (11b″) D-Bc-, (11c″) D-Ba-Bc-, (11d″) D-Bc-Ba-Bc-, (11e″)D-Bc-Bc-Ba-Bc-, (11f″) D-Ba-Bc-Bc-Ba-Bc-, (11g″) D-Ba-Ba-Bc-Bc-Ba-Bc-,(11h″) D-Bt-Ba-Ba-Bc-Bc-Ba-Bc-, (11i″) D-Bg-Bt-Ba-Ba-Bc-Bc-Ba-Bc-, or(11j″) D-Ba-Bg-Bt-Ba-Ba-Bc-Bc-Ba-Bc-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); Bt is a grouprepresented by the following formula (U1) or (T2); and D is HO— or Ph-wherein Ph- is a group represented by the following first formula:

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″11) is a group represented by the following formula (11″):

(11″) (SEQ ID NO: 138) -Ba-Bg-Bg-Bt-Bt-Bg-Bt-Bg-Bt-Bc-Ba-where Bg, Ba, Bt and Bc are as defined above;B_(B″11) is a group represented by any one of the following (111a″) to(111j″):

(111a″)- CH₂CH₂OH, (111b″)- Bc-CH₂CH₂OH, (111c″)- Bc-Bc-CH₂CH₂OH,(111d″)- Bc-Bc-Ba-CH₂CH₂OH, (111e″)- Bc-Bc-Ba-Bg-CH₂CH₂OH, (111f″)-Bc-Bc-Ba-Bg-Ba-CH₂CH₂OH, (111g″)- Bc-Bc-Ba-Bg-Ba-Bg-CH₂CH₂OH, (111h″)-Bc-Bc-Ba-Bg-Ba-Bg-Bt-CH₂CH₂OH, (111i″)-Bc-Bc-Ba-Bg-Ba-Bg-Bt-Ba-CH₂CH₂OH, or (111j″)-Bc-Bc-Ba-Bg-Ba-Bg-Bt-Ba-Ba-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (XI″) has 2″-O,4″-C-alkylene group.[37] A compound represented by the following general formula (XII″) or apharmacologically acceptable salt thereof:

(XII″) B_(T″12)-B_(M″12)-B_(B″12)where B_(T″12) is a group represented by any one of the following (12a″)to (12j″):

(12a″) D-, (12b″) D-Bt-, (12c″) D-Ba-Bt-, (12d″) D-Bc-Ba-Bt-, (12e″)D-Bc-Bc-Ba-Bt-, (12f″) D-Ba-Bc-Bc-Ba-Bt-, (12g″) D-Bc-Ba-Bc-Bc-Ba-Bt-,(12h″) D-Bc-Bc-Ba-Bc-Bc-Ba-Bt-, (12i″) D-Bc-Bc-Bc-Ba-Bc-Bc-Ba-Bt-, or(12j″) D-Ba-Bc-Bc-Bc-Ba-Bc-Bc-Ba-Bt-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); Bt is a grouprepresented by the following formula (U1) or (T2); and D is HO— or Ph-wherein Ph- is a group represented by the following first formula:

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″12) is a group represented by the following formula (12″):

(12″) (SEQ ID NO: 139) -Bc-Ba-Bc-Bc-Bc-Bt-Bc-Bt-Bg-Bt-Bg-where Bg, Ba, Bt and Bc are as defined above;B_(B″12) is a group represented by any one of the following(112a″)˜(112j″):

(112a″)- CH₂CH₂OH, (112b″)- Ba-CH₂CH₂OH, (112c″)- Ba-Bt-CH₂CH₂OH,(112d″)- Ba-Bt-Bt-CH₂CH₂OH, (112e″)- Ba-Bt-Bt-Bt-CH₂CH₂OH, (112f″)-Ba-Bt-Bt-Bt-Bt-CH₂CH₂OH, (112g″)- Ba-Bt-Bt-Bt-Bt-Ba-CH₂CH₂OH, (112h″)-Ba-Bt-Bt-Bt-Bt-Ba-Bt-CH₂CH₂OH, (112i″)-Ba-Bt-Bt-Bt-Bt-Ba-Bt-Ba-CH₂CH₂OH, or (112j″)- (SEQ ID NO: 140)Ba-Bt-Bt-Bt-Bt-Ba-Bt-Ba-Ba-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (XII″) has 2″-O,4″-C-alkylene group.[38] A compound represented by the following general formula (XIII″) ora pharmacologically acceptable salt thereof:

(XIII″) B_(T″13)-B_(M″13)-B_(B″13)where B_(T″13) is a group represented by any one of the following (13a″)to (13k″):

(13a″) HO-, (13b″) HO-Bc-, (13c″) HO-Bt-Bc-, (13d″) HO-Bg-Bt-Bc-, (13e″)HO-Bg-Bg-Bt-Bc-, (13f″) HO-Ba-Bg-Bg-Bt-Bc-, (13g″)HO-Ba-Ba-Bg-Bg-Bt-Bc-, (13h″) HO-Bc-Ba-Ba-Bg-Bg-Bt-Bc-, (13i″)HO-Bt-Bc-Ba-Ba-Bg-Bg-Bt-Bc-, (13j″) HO-Bc-Bt-Bc-Ba-Ba-Bg-Bg-Bt-Bc-, or(13k″) HO-Bc-Bc-Bt-Bc-Ba-Ba-Bg-Bg-Bt-Bc-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″13) is a group represented by the following formula (13″):

(13″) (SEQ ID NO: 141) -Ba-Bc-Bc-Bc-Ba-Bc-Bc-Ba-Bt-Bc-where Bg, Ba, Bt and Bc are as defined above;B_(B″13) is a group represented by the following (113a″):

(113a″)- CH₂CH₂OHprovided that at least one of the nucleosides constituting the compoundrepresented by formula (XIII″) has 2″-O,4″-C-alkylene group.[39] A compound represented by the following general formula (XIV″) or apharmacologically acceptable salt thereof:

(XIV″) B_(T″14)-B_(M″14)-B_(B″14)where B_(T″14) is a group represented by any one of the following (14a″)to (14q″):

(14a″) HO-, (14b″) HO-Ba-, (14c″) HO-Ba-Ba-, (14d″) HO-Bg-Ba-Ba-, (14e″)HO-Ba-Bg-Ba-Ba-, (14f″) HO-Bg-Ba-Bg-Ba-Ba-, (14g″)HO-Ba-Bg-Ba-Bg-Ba-Ba-, (14h″) HO-Bc-Ba-Bg-Ba-Bg-Ba-Ba-, (14i″)HO-Bg-Bc-Ba-Bg-Ba-Bg-Ba-Ba-, (14j″) HO-Ba-Bg-Bc-Ba-Bg-Ba-Bg-Ba-Ba-,(14k″) (SEQ ID NO: 142) HO-Ba-Ba-Bg-Bc-Ba-Bg-Ba-Bg-Ba-Ba-, (14l″) (SEQID NO: 143) HO-Bc-Ba-Ba-Bg-Bc-Ba-Bg-Ba-Bg-Ba-Ba-, (14m″) (SEQ ID NO:144) HO-Bt-Bc-Ba-Ba-Bg-Bc-Ba-Bg-Ba-Bg-Ba-Ba-, (14n″) (SEQ ID NO: 145)HO-Ba-Bt-Bc-Ba-Ba-Bg-Bc-Ba-Bg-Ba-Bg-Ba-Ba-, (14o″) (SEQ ID NO: 146)HO-Bg-Ba-Bt-Bc-Ba-Ba-Bg-Bc-Ba-Bg-Ba-Bg-Ba-Ba-, (14p″) (SEQ ID NO: 147)HO-Bt-Bg-Ba-Bt-Bc-Ba-Ba-Bg-Bc-Ba-Bg-Ba-Bg-Ba-Ba-, or (14q″) (SEQ ID NO:148) HO-Bt-Bt-Bg-Ba-Bt-Bc-Ba-Ba-Bg-Bc-Ba-Bg-Ba-Bg-Ba- Ba-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″14) is a group represented by the following formula (14″):

(14″) -Ba-Bg-Bc-Bc-where Bg, Ba, Bt and Bc are as defined above;B_(B″14) is a group represented by any one of the following (114a″) to(114o″):

(114a″)- CH₂CH₂OH, (114b″)- Ba-CH₂CH₂OH, (114c″)- Ba-Bg-CH₂CH₂OH,(114d″)- Ba-Bg-Bt-CH₂CH₂OH, (114e″)- Ba-Bg-Bt-Bc-CH₂CH₂OH, (114f″)-Ba-Bg-Bt-Bc-Bg-CH₂CH₂OH, (114g″)- Ba-Bg-Bt-Bc-Bg-Bg-CH₂CH₂OH, (114h″)-Ba-Bg-Bt-Bc-Bg-Bg-Bt-CH₂CH₂OH, (114i″)-Ba-Bg-Bt-Bc-Bg-Bg-Bt-Ba-CH₂CH₂OH, (114j″)-Ba-Bg-Bt-Bc-Bg-Bg-Bt-Ba-Ba-CH₂CH₂OH, (114k″)- (SEQ ID NO: 149)Ba-Bg-Bt-Bc-Bg-Bg-Bt-Ba-Ba-Bg-CH₂CH₂OH, (114l″)- (SEQ ID NO: 150)Ba-Bg-Bt-Bc-Bg-Bg-Bt-Ba-Ba-Bg-Bt-CH₂CH₂OH, (114m″)- (SEQ ID NO: 151)Ba-Bg-Bt-Bc-Bg-Bg-Bt-Ba-Ba-Bg-Bt-Bt-CH₂CH₂OH, (114n″)- (SEQ ID NO: 152)Ba-Bg-Bt-Bc-Bg-Bg-Bt-Ba-Ba-Bg-Bt-Bt-Bc-CH₂CH₂OH, or (114o″)- (SEQ ID NO:153) Ba-Bg-Bt-Bc-Bg-Bg-Bt-Ba-Ba-Bg-Bt-Bt-Bc-Bt-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (XIV″) has 2″-O,4″-C-alkylene group.[40] A compound represented by the following general formula (XV″) or apharmacologically acceptable salt thereof:

(XV″) B_(T″15)-B_(M″15)-B_(B″15)where B_(T″15) is a group represented by any one of the following (15a″)to (15j″):

(15a″) HO-, (15b″) HO-Bt-, (15c″) HO-Bc-Bt-, (15d″) HO-Bt-Bc-Bt-, (15e″)HO-Bt-Bt-Bc-Bt-, (15f″) HO-Bt-Bt-Bt-Bc-Bt-, (15g″)HO-Ba-Bt-Bt-Bt-Bc-Bt-, (15h″) HO-Bc-Ba-Bt-Bt-Bt-Bc-Bt-, (15i″)HO-Bg-Bc-Ba-Bt-Bt-Bt-Bc-Bt-, or (15j″) HO-Bg-Bg-Bc-Ba-Bt-Bt-Bt-Bc-Bt-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″15) is a group represented by the following formula (15″):

(15″) -Ba-Bg-Bt-Bt-Bt-Bg-Bg-Ba-Bg-where Bg, Ba, Bt and Bc are as defined above;B_(B″15) is a group represented by any one of the following (115a″) to(115j″):

(115a″)- CH₂CH₂OH, (115b″)- Ba-CH₂CH₂OH, (115c″)- Ba-Bt-CH₂CH₂OH,(115d″)- Ba-Bt-Bg-CH₂CH₂OH, (115e″)- Ba-Bt-Bg-Bg-CH₂CH₂OH, (115f″)-Ba-Bt-Bg-Bg-Bc-CH₂CH₂OH, (115g″)- Ba-Bt-Bg-Bg-Bc-Ba-CH₂CH₂OH, (115h″)-Ba-Bt-Bg-Bg-Bc-Ba-Bg-CH₂CH₂OH, (115i″)-Ba-Bt-Bg-Bg-Bc-Ba-Bg-Bt-CH₂CH₂OH, or (115j″)-Ba-Bt-Bg-Bg-Bc-Ba-Bg-Bt-Bt-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above; provided that at least oneof the nucleosides constituting the compound represented by formula(XV″) has 2″-O,4″-C-alkylene group.[41] A compound represented by the following general formula (XVI″) or apharmacologically acceptable salt thereof:

(XVI″) B_(T″16)-B_(M″16)-B_(B″16)where B_(T″16) is a group represented by any one of the following (16a″)to (16j″):

(16a″) HO-, (16b″) HO-Bg-, (16c″) HO-Bt-Bg-, (16d″) HO-Bg-Bt-Bg-, (16e″)HO-Bg-Bg-Bt-Bg-, (16f″) HO-Ba-Bg-Bg-Bt-Bg-, (16g″)HO-Ba-Ba-Bg-Bg-Bt-Bg-, (16h″) HO-Bg-Ba-Ba-Bg-Bg-Bt-Bg-, (16i″)HO-Bt-Bg-Ba-Ba-Bg-Bg-Bt-Bg-, or (16j″) HO-Bc-Bt-Bg-Ba-Ba-Bg-Bg-Bt-Bg-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″16) is a group represented by the following formula (16″):

(16″) -Bt-Bt-Bc-Bt-Bt-Bg-Bt-Ba-Bc-where Bg, Ba, Bt and Bc are as defined above;B_(B″16) is a group represented by any one of the following (116a″) to(116j″):

(116a″)- CH₂CH₂OH, (116b″)- Bt-CH₂CH₂OH, (116c″)- Bt-Bt-CH₂CH₂OH,(116d″)- Bt-Bt-Bc-CH₂CH₂OH, (116e″)- Bt-Bt-Bc-Ba-CH₂CH₂OH, (116f″)-Bt-Bt-Bc-Ba-Bt-CH₂CH₂OH, (116g″)- Bt-Bt-Bc-Ba-Bt-Bc-CH₂CH₂OH, (116h″)-Bt-Bt-Bc-Ba-Bt-Bc-Bc-CH₂CH₂OH, (116i″)-Bt-Bt-Bc-Ba-Bt-Bc-Bc-Bc-CH₂CH₂OH, or (116j″)-Bt-Bt-Bc-Ba-Bt-Bc-Bc-Bc-Ba-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (XVI″) has 2″-O,4″-C-alkylene group.[42] A compound represented by the following general formula (XVII″) ora pharmacologically acceptable salt thereof:

(XVII″) B_(T″17)-B_(M″17)-B_(B″17)where B_(T″17) is a group represented by any one of the following (17a″)to (17j″):

(17a″) HO-, (17b″) HO-Bt-, (17c″) HO-Bt-Bt-, (17d″) HO-Bg-Bt-Bt-, (17e″)HO-Bg-Bg-Bt-Bt-, (17f″) HO-Bc-Bg-Bg-Bt-Bt-, (17g″)HO-Bc-Bc-Bg-Bg-Bt-Bt-, (17h″) HO-Bt-Bc-Bc-Bg-Bg-Bt-Bt-, (17i″)HO-Bc-Bt-Bc-Bc-Bg-Bg-Bt-Bt-, or (17j″) HO-Bc-Bc-Bt-Bc-Bc-Bg-Bg-Bt-Bt-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″17) is a group represented by the following formula (17″):

(17″) -Bc-Bt-Bg-Ba-Ba-Bg-Bg-Bt-Bg-where Bg, Ba, Bt and Bc are as defined above;B_(B″17) is a group represented by any one of the following (117a″) to(117j″):

(117a″)- CH₂CH₂OH, (117b″)- Bt-CH₂CH₂OH, (117c″)- Bt-Bt-CH₂CH₂OH,(117d″)- Bt-Bt-Bc-CH₂CH₂OH, (117e″)- Bt-Bt-Bc-Bt-CH₂CH₂OH, (117f″)-Bt-Bt-Bc-Bt-Bt-CH₂CH₂OH, (117g″)- Bt-Bt-Bc-Bt-Bt-Bg-CH₂CH₂OH, (117h″)-Bt-Bt-Bc-Bt-Bt-Bg-Bt-CH₂CH₂OH, (117i″)-Bt-Bt-Bc-Bt-Bt-Bg-Bt-Ba-CH₂CH₂OH, or (117j″)-Bt-Bt-Bc-Bt-Bt-Bg-Bt-Ba-Bc-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (XVII″) has 2″-O,4″-C-alkylene group.[43] A compound represented by the following general formula (XVIII″) ora pharmacologically acceptable salt thereof:

(XVIII″) B_(T″18)-B_(M″18)-B_(B″18)where B_(T″18) is a group represented by any one of the following (18a″)to (18j″):

(18a″) HO-, (18b″) HO-Bg-, (18c″) HO-Bt-Bg-, (18d″) HO-Bc-Bt-Bg-, (18e″)HO-Bc-Bc-Bt-Bg-, (18f″) HO-Ba-Bc-Bc-Bt-Bg-, (18g″)HO-Bg-Ba-Bc-Bc-Bt-Bg-, (18h″) HO-Ba-Bg-Ba-Bc-Bc-Bt-Bg-, (18i″)HO-Ba-Ba-Bg-Ba-Bc-Bc-Bt-Bg-, or (18j″) HO-Bt-Ba-Ba-Bg-Ba-Bc-Bc-Bt-Bg-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″18) is a group represented by the following formula (18″):

(18″) -Bc-Bt-Bc-Ba-Bg-Bc-Bt-Bt-Bc-where Bg, Ba, Bt and Bc are as defined above;B_(B″18) is a group represented by any one of the following (118a″) to(118j″):

(118a″)- CH₂CH₂OH, (118b″)- Bt-CH₂CH₂OH, (118c″)- Bt-Bt-CH₂CH₂OH,(118d″)- Bt-Bt-Bc-CH₂CH₂OH, (118e″)- Bt-Bt-Bc-Bc-CH₂CH₂OH, (118f″)-Bt-Bt-Bc-Bc-Bt-CH₂CH₂OH, (118g″)- Bt-Bt-Bc-Bc-Bt-Bt-CH₂CH₂OH, (118h″)-Bt-Bt-Bc-Bc-Bt-Bt-Ba-CH₂CH₂OH, (118i″)-Bt-Bt-Bc-Bc-Bt-Bt-Ba-Bg-CH₂CH₂OH, or (118j″)-Bt-Bt-Bc-Bc-Bt-Bt-Ba-Bg-Bc-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (XVIII″) has 2″-O,4″-C-alkylene group.[44] A compound represented by the following general formula (XIX″) or apharmacologically acceptable salt thereof:

(XIX″) B_(T″19)-B_(M″19)-B_(B″19)where B_(T″19) is a group represented by any one of the following (19a″)to (19j″):

(19a″) HO-, (19b″) HO-Bc-, (19c″) HO-Bg-Bc-, (19d″) HO-Ba-Bg-Bc-, (19e″)HO-Bt-Ba-Bg-Bc-, (19f″) HO-Bt-Bt-Ba-Bg-Bc-, (19g″)HO-Bc-Bt-Bt-Ba-Bg-Bc-, (19h″) HO-Bc-Bc-Bt-Bt-Ba-Bg-Bc-, (19i″)HO-Bt-Bc-Bc-Bt-Bt-Ba-Bg-Bc-, or (19j″) HO-Bt-Bt-Bc-Bc-Bt-Bt-Ba-Bg-Bc-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″19) is a group represented by the following formula (19″):

(19″) -Bt-Bt-Bc-Bc-Ba-Bg-Bc-Bc-Ba-where Bg, Ba, Bt and Bc are as defined above;B_(B″19) is a group represented by any one of the following (119a″) to(119j″):

(119a″)- CH₂CH₂OH, (119b″)- Bt-CH₂CH₂OH, (119c″)- Bt-Bt-CH₂CH₂OH,(119d″)- Bt-Bt-Bg-CH₂CH₂OH, (119e″)- Bt-Bt-Bg-Bt-CH₂CH₂OH, (119f″)-Bt-Bt-Bg-Bt-Bg-CH₂CH₂OH, (119g″)- Bt-Bt-Bg-Bt-Bg-Bt-CH₂CH₂OH, (119h″)-Bt-Bt-Bg-Bt-Bg-Bt-Bt-CH₂CH₂OH, (119i″)-Bt-Bt-Bg-Bt-Bg-Bt-Bt-Bg-CH₂CH₂OH, or (119j″)-Bt-Bt-Bg-Bt-Bg-Bt-Bt-Bg-Ba-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above; provided that at least oneof the nucleosides constituting the compound represented by formula(XIX″) has 2″-O,4″-C-alkylene group.[45] A compound represented by the following general formula (XX″) or apharmacologically acceptable salt thereof:

(XX″) B_(T″20)-B_(M″20)-B_(B″20)where B_(T″20) is a group represented by any one of the following (20a″)to (20j″):

(20a″) HO-, (20b″) HO-Bc-, (20c″) HO-Bt-Bc-, (20d″) HO-Bt-Bt-Bc-, (20e″)HO-Bc-Bt-Bt-Bc-, (20f″) HO-Bg-Bc-Bt-Bt-Bc-, (20g″)HO-Ba-Bg-Bc-Bt-Bt-Bc-, (20h″) HO-Bc-Ba-Bg-Bc-Bt-Bt-Bc-, (20i″)HO-Bt-Bc-Ba-Bg-Bc-Bt-Bt-Bc-, or (20j″) HO-Bc-Bt-Bc-Ba-Bg-Bc-Bt-Bt-Bc-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″20) is a group represented by the following formula (20″):

(20″) -Bt-Bt-Bc-Bc-Bt-Bt-Ba-Bg-Bc-where Bg, Ba, Bt and Bc are as defined above;B_(B″20) is a group represented by any one of the following (120a″) to(120j″):

(120a″)- CH₂CH₂OH, (120b″)- Bt-CH₂CH₂OH, (120c″)- Bt-Bt-CH₂CH₂OH,(120d″)- Bt-Bt-Bc-CH₂CH₂OH, (120e″)- Bt-Bt-Bc-Bc-CH₂CH₂OH, (120f″)-Bt-Bt-Bc-Bc-Ba-CH₂CH₂OH, (120g″)- Bt-Bt-Bc-Bc-Ba-Bg-CH₂CH₂OH, (120h″)-Bt-Bt-Bc-Bc-Ba-Bg-Bc-CH₂CH₂OH, (120i″)-Bt-Bt-Bc-Bc-Ba-Bg-Bc-Bc-CH₂CH₂OH, or (120j″)-Bt-Bt-Bc-Bc-Ba-Bg-Bc-Bc-Ba-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (XX″) has 2″-O,4″-C-alkylene group.[46] A compound represented by the following general formula (XXI″) or apharmacologically acceptable salt thereof:

(XXI″) B_(T″21)-B_(M″21)-B_(B″21)where B_(T″21) is a group represented by any one of the following (21a″)to (21e″):

(21a″) HO-, (21b″) HO-Ba-, (21c″) HO-Bc-Ba-, (21d″) HO-Bt-Bc-Ba-, or(21e″) HO-Bc-Bt-Bc-Ba-where Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); and Bt is agroup represented by the following formula (U1) or (T2):

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms;B_(M″21) is a group represented by the following formula (21″):

(21″) (SEQ ID NO: 154) -Bg-Bc-Bt-Bt-Bc-Bt-Bt-Bc-Bc-Bt-Bt-Ba-Bg-Bc-where Bg, Ba, Bt and Bc are as defined above;B_(B″21) is a group represented by any one of the following (121a″) to(121e″):

(121a″)- CH₂CH₂OH, (121b″)- Bt-CH₂CH₂OH, (121c″)- Bt-Bt-CH₂CH₂OH,(121d″)- Bt-Bt-Bc-CH₂CH₂OH, or (121e″)- Bt-Bt-Bc-Bc-CH₂CH₂OHwhere Bg, Ba, Bt and Bc are as defined above;provided that at least one of the nucleosides constituting the compoundrepresented by formula (XXI″) has 2″-O,4″-C-alkylene group.[47] The compound of any one of [26] to [46] above which is selectedfrom the group consisting of the following compounds (i″) to (xlix″), ora pharmacologically acceptable salt thereof:(i″) a compound represented by the following formula (i″):

(i″) (SEQ ID NO: 155) HO-Bg-Ba-Ba-Ba-Ba-Bc-Bg-Bc-Bc-Bg-Bc-Bc-Ba-Bt-Bt-Bt-Bc-Bt-CH₂CH₂OH(ii″) a compound represented by the following formula (ii″):

(ii″) (SEQ ID NO: 156) HO-Bc-Bt-Bg-Bt-Bt-Ba-Bg-Bc-Bc-Ba-Bc-Bt-Bg-Ba-Bt-Bt-Ba-Ba-CH₂CH₂OH(iii″) a compound represented by the following formula (iii″):

(iii″) (SEQ ID NO: 157) HO-Bt-Bg-Ba-Bg-Ba-Ba-Ba-Bc-Bt-Bg-Bt-Bt-Bc-Ba-Bg-Bc-Bt-Bt-CH₂CH₂OH(iv″) a compound represented by the following formula (iv″):

(iv″) (SEQ ID NO: 158) HO-Bc-Ba-Bg-Bg-Ba-Ba-Bt-Bt-Bt-Bg-Bt-Bg-Bt-Bc-Bt-Bt-Bt-Bc-CH₂CH₂OH(v″) a compound represented by the following formula (v″):

(v″) (SEQ ID NO: 159) HO-Bg-Bt-Ba-Bt-Bt-Bt-Ba-Bg-Bc-Ba-Bt-Bg-Bt-Bt-Bc-Bc-Bc-Ba-CH₂CH₂OH(vi″) a compound represented by the following formula (vi″):

(vi″) (SEQ ID NO: 160) HO-Ba-Bg-Bc-Ba-Bt-Bg-Bt-Bt-Bc-Bc-Bc-Ba-Ba-Bt-Bt-Bc-Bt-Bc-CH₂CH₂OH(vii″) a compound represented by the following formula (vii″):

(vii″) (SEQ ID NO: 161) HO-Bg-Bc-Bc-Bg-Bc-Bc-Ba-Bt-Bt-Bt-Bc-Bt-Bc-Ba-Ba-Bc-Ba-Bg-CH₂CH₂OH(viii″) a compound represented by the following formula (viii″):

(viii″) (SEQ ID NO: 37) HO-Bc-Ba-Bt-Ba-Ba-Bt-Bg-Ba-Ba-Ba-Ba-Bc-Bg-Bc-Bc-Bg-Bc-Bc-CH₂CH₂OH(ix″) a compound represented by the following formula (ix″):

(ix″) (SEQ ID NO: 162) HO-Bt-Bt-Bc-Bc-Bc-Ba-Ba-Bt-Bt-Bc-Bt-Bc-Ba-Bg-Bg-Ba-Ba-Bt-CH₂CH₂OH(x″) a compound represented by the following formula (x″):

(x″) (SEQ ID NO: 163) HO-Bc-Bc-Ba-Bt-Bt-Bt-Bg-Bt-Ba-Bt-Bt-Bt-Ba-Bg-Bc-Ba-Bt-Bg-CH₂CH₂OH(xi″) a compound represented by the following formula (xi″):

(xi″) (SEQ ID NO: 164) HO-Bc-Bt-Bc-Ba-Bg-Ba-Bt-Bc-Bt-Bt-Bc-Bt-Ba-Ba-Bc-Bt-Bt-Bc-CH₂CH₂OH(xii″) a compound represented by the following formula (xii″):

(xii″) (SEQ ID NO: 165) HO-Ba-Bc-Bc-Bg-Bc-Bc-Bt-Bt-Bc-Bc-Ba-Bc-Bt-Bc-Ba-Bg-Ba-Bg-CH₂CH₂OH(xiii″) a compound represented by the following formula (xiii″):

(xiii″) (SEQ ID NO: 166)HO-Bt-Bc-Bt-Bt-Bg-Ba-Ba-Bg-Bt-Ba-Ba-Ba-Bc-Bg-Bg- Bt-Bt-Bt-CH₂CH₂OH(xiv″) a compound represented by the following formula (xiv″):

(xiv″) (SEQ ID NO: 167) HO-Bg-Bg-Bc-Bt-Bg-Bc-Bt-Bt-Bt-Bg-Bc-Bc-Bc-Bt-Bc-Ba-Bg-Bc-CH₂CH₂OH(xv″) a compound represented by the following formula (XV″):

(xv″) (SEQ ID NO: 44) HO-Ba-Bg-Bt-Bc-Bc-Ba-Bg-Bg-Ba-Bg-Bc-Bt-Ba-Bg-Bg-Bt-Bc-Ba-CH₂CH₂OH(xvi″) a compound represented by the following formula (xvi″):

(xvi″) (SEQ ID NO: 45) HO-Bg-Bc-Bt-Bc-Bc-Ba-Ba-Bt-Ba-Bg-Bt-Bg-Bg-Bt-Bc-Ba-Bg-Bt-CH₂CH₂OH(xvii″) a compound represented by the following formula (xvii″):

(xvii″) (SEQ ID NO: 168)HO-Bg-Bc-Bt-Ba-Bg-Bg-Bt-Bc-Ba-Bg-Bg-Bc-Bt-Bg-Bc- Bt-Bt-Bt-CH₂CH₂OH(xviii″) a compound represented by the following formula (xviii″):

(xviii″) (SEQ ID NO: 169)HO-Bg-Bc-Ba-Bg-Bc-Bc-Bt-Bc-Bt-Bc-Bg-Bc-Bt-Bc-Ba- Bc-Bt-Bc-CH₂CH₂OH(xix″) a compound represented by the following formula (xix″):

(xix″) (SEQ ID NO: 170) HO-Bt-Bc-Bt-Bt-Bc-Bc-Ba-Ba-Ba-Bg-Bc-Ba-Bg-Bc-Bc-Bt-Bc-Bt-CH₂CH₂OH(xx″) a compound represented by the following formula (XX″):

(xx″) (SEQ ID NO: 171) HO-Bt-Bg-Bc-Ba-Bg-Bt-Ba-Ba-Bt-Bc-Bt-Ba-Bt-Bg-Ba-Bg-Bt-Bt-CH₂CH₂OH(xxi″) a compound represented by the following formula (xxi″):

(xxi″) (SEQ ID NO: 172) HO-Bg-Bt-Bt-Bt-Bc-Ba-Bg-Bc-Bt-Bt-Bc-Bt-Bg-Bt-Ba-Ba-Bg-Bc-CH₂CH₂OH(xxii″) a compound represented by the following formula (xxii″):

(xxii″) (SEQ ID NO: 51) HO-Bt-Bg-Bt-Ba-Bg-Bg-Ba-Bc-Ba-Bt-Bt-Bg-Bg-Bc-Ba-Bg-Bt-Bt-CH₂CH₂OH(xxiii″) a compound represented by the following formula (xxiii″):

(xxiii″) (SEQ ID NO: 173)HO-Bt-Bc-Bc-Bt-Bt-Ba-Bc-Bg-Bg-Bg-Bt-Ba-Bg-Bc-Ba- Bt-Bc-Bc-CH₂CH₂OH(xxiv″) a compound represented by the following formula (xxiv″):

(xxiv″) (SEQ ID NO: 174)HO-Ba-Bg-Bc-Bt-Bc-Bt-Bt-Bt-Bt-Ba-Bc-Bt-Bc-Bc-Bc- Bt-Bt-Bg-CH₂CH₂OH(xxv″) a compound represented by the following formula (xxv″):

(xxv″) (SEQ ID NO: 175) HO-Bc-Bc-Ba-Bt-Bt-Bg-Bt-Bt-Bt-Bc-Ba-Bt-Bc-Ba-Bg-Bc-Bt-Bc-CH₂CH₂OH(xxvi″) a compound represented by the following formula (xxvi″):

(xxvi″) (SEQ ID NO: 55) HO-Bc-Bt-Ba-Bt-Bg-Ba-Bg-Bt-Bt-Bt-Bc-Bt-Bt-Bc-Bc-Ba-Ba-Ba-CH₂CH₂OH(xxvii″) a compound represented by the following formula (xxvii″):

(xxvii″) (SEQ ID NO: 176)D-Bt-Bg-Bt-Bg-Bt-Bc-Ba-Bc-Bc-Ba-Bg-Ba-Bg-Bt-Ba-Ba- Bc-Ba-Bg-Bt-CH₂CH₂OH(xxviii″) a compound represented by the following formula (xxviii″):

(xxviii″) (SEQ ID NO: 177)D-Ba-Bg-Bg-Bt-Bt-Bg-Bt-Bg-Bt-Bc-Ba-Bc-Bc-Ba-Bg-Ba- Bg-Bt-Ba-Ba-CH₂CH₂OH(xxix″) a compound represented by the following formula (xxix″):

(xxix″) (SEQ ID NO: 178)D-Ba-Bg-Bt-Ba-Ba-Bc-Bc-Ba-Bc-Ba-Bg-Bg-Bt-Bt-Bg-Bt- Bg-Bt-Bc-Ba-CH₂CH₂OH(xxx″) a compound represented by the following formula (XXX″):

(xxx″) (SEQ ID NO: 59)D-Bt-Bt-Bg-Ba-Bt-Bc-Ba-Ba-Bg-Bc-Ba-Bg-Ba-Bg-Ba-Ba- Ba-Bg-Bc-Bc-CH₂CH₂OH(xxxi″) a compound represented by the following formula (xxxi″):

(xxxi″) (SEQ ID NO: 179)D-Bc-Ba-Bc-Bc-Bc-Bt-Bc-Bt-Bg-Bt-Bg-Ba-Bt-Bt-Bt-Bt- Ba-Bt-Ba-Ba-CH₂CH₂OH(xxxii″) a compound represented by the following formula (xxxii″):

(xxxii″) (SEQ ID NO: 180)D-Ba-Bc-Bc-Bc-Ba-Bc-Bc-Ba-Bt-Bc-Ba-Bc-Bc-Bc-Bt-Bc- Bt-Bg-Bt-Bg-CH₂CH₂OH(xxxiii″) a compound represented by the following formula (xxxiii″):

(xxxiii″) (SEQ ID NO: 181)D-Bc-Bc-Bt-Bc-Ba-Ba-Bg-Bg-Bt-Bc-Ba-Bc-Bc-Bc-Ba-Bc- Bc-Ba-Bt-Bc-CH₂CH₂OH(xxxiv″) a compound represented by the following formula (xxxiv″):

(xxxiv″) (SEQ ID NO: 182)HO-Bt-Ba-Ba-Bc-Ba-Bg-Bt-Bc-Bt-Bg-Ba-Bg-Bt-Ba-Bg- Bg-Ba-Bg-CH₂CH₂OH(xxxv″) a compound represented by the following formula (xxxv″):

(xxxv″) (SEQ ID NO: 183)HO-Bg-Bg-Bc-Ba-Bt-Bt-Bt-Bc-Bt-Ba-Bg-Bt-Bt-Bt-Bg- Bg-Ba-Bg-CH₂CH₂OH(xxxvi″) a compound represented by the following formula (xxxvi″):

(xxxvi″) (SEQ ID NO: 184)HO-Ba-Bg-Bc-Bc-Ba-Bg-Bt-Bc-Bg-Bg-Bt-Ba-Ba-Bg-Bt- Bt-Bc-Bt-CH₂CH₂OH(xxxvii″) a compound represented by the following formula (xxxvii″):

(xxxvii″) (SEQ ID NO: 185)HO-Ba-Bg-Bt-Bt-Bt-Bg-Bg-Ba-Bg-Ba-Bt-Bg-Bg-Bc-Ba- Bg-Bt-Bt-CH₂CH₂OH(xxxviii″) a compound represented by the following formula (xxxviii″):

(xxxviii″) (SEQ ID NO: 186)HO-Bc-Bt-Bg-Ba-Bt-Bt-Bc-Bt-Bg-Ba-Ba-Bt-Bt-Bc-Bt- Bt-Bt-Bc-CH₂CH₂OH(xxxix″) a compound represented by the following formula (xxxix″):

(xxxix″) (SEQ ID NO: 68)HO-Bt-Bt-Bc-Bt-Bt-Bg-Bt-Ba-Bc-Bt-Bt-Bc-Ba-Bt-Bc- Bc-Bc-Ba-CH₂CH₂OH(xl″) a compound represented by the following formula (xl″):

(xl″) (SEQ ID NO: 187) HO-Bc-Bc-Bt-Bc-Bc-Bg-Bg-Bt-Bt-Bc-Bt-Bg-Ba-Ba-Bg-Bg-Bt-Bg-CH₂CH₂OH(xli″) a compound represented by the following formula (xli″):

(xli″) (SEQ ID NO: 188) HO-Bc-Ba-Bt-Bt-Bt-Bc-Ba-Bt-Bt-Bc-Ba-Ba-Bc-Bt-Bg-Bt-Bt-Bg-CH₂CH₂OH(xlii″) a compound represented by the following formula (xlii″):

(xlii″) (SEQ ID NO: 189)HO-Bt-Bt-Bc-Bc-Bt-Bt-Ba-Bg-Bc-Bt-Bt-Bc-Bc-Ba-Bg- Bc-Bc-Ba-CH₂CH₂OH(xliii″) a compound represented by the following formula (xliii″):

(xliii″) (SEQ ID NO: 190)HO-Bt-Ba-Ba-Bg-Ba-Bc-Bc-Bt-Bg-Bc-Bt-Bc-Ba-Bg-Bc- Bt-Bt-Bc-CH₂CH₂OH(xliv″) a compound represented by the following formula (xliv″):

(xliv″) (SEQ ID NO: 191)HO-Bc-Bt-Bt-Bg-Bg-Bc-Bt-Bc-Bt-Bg-Bg-Bc-Bc-Bt-Bg- Bt-Bc-Bc-CH₂CH₂OH(xlv″) a compound represented by the following formula (xlv″):

(xlv″) (SEQ ID NO: 192) HO-Bc-Bt-Bc-Bc-Bt-Bt-Bc-Bc-Ba-Bt-Bg-Ba-Bc-Bt-Bc-Ba-Ba-Bg-CH₂CH₂OH(xlvi″) a compound represented by the following formula (xlvi″):

(xlvi″) (SEQ ID NO: 75) HO-Bc-Bt-Bg-Ba-Ba-Bg-Bg-Bt-Bg-Bt-Bt-Bc-Bt-Bt-Bg-Bt-Ba-Bc-CH₂CH₂OH(xlvii″) a compound represented by the following formula (xlvii″):

(xlvii″) (SEQ ID NO: 76)HO-Bt-Bt-Bc-Bc-Ba-Bg-Bc-Bc-Ba-Bt-Bt-Bg-Bt-Bg-Bt- Bt-Bg-Ba-CH₂CH₂OH(xlviii″) a compound represented by the following formula (xlviii″):

(xlviii″) (SEQ ID NO: 193)HO-Bc-Bt-Bc-Ba-Bg-Bc-Bt-Bt-Bc-Bt-Bt-Bc-Bc-Bt-Bt- Ba-Bg-Bc-CH₂CH₂OH(xlix″) a compound represented by the following formula (xlix″):

(xlix″) (SEQ ID NO: 194)HO-Bg-Bc-Bt-Bt-Bc-Bt-Bt-Bc-Bc-Bt-Bt-Ba-Bg-Bc-Bt- Bt-Bc-Bc-CH₂CH₂OHwhere Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); Bt is a grouprepresented by the following formula (U1) or (T2); and D is HO— or Ph-wherein Ph- is a group represented by the following first formula:

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms.[48] The compound of any one of [26] to [46] above which is selectedfrom the group consisting of the following compounds (i″-a) to (li″-a),or a pharmacologically acceptable salt thereof:(i″-a) a compound represented by the following formula (i″-a):

(i″-a) (SEQ ID NO: 30) HO-Bg-Ba-Ba-Ba-Ba-Bc-Bg-Bc-Bc-Bg-Bc-Bc-Ba-B′t-B′u-B′u-Bc-B′t-CH₂CH₂OH(ii″-a) a compound represented by the following formula (ii″-a):

(ii″-a) (SEQ ID NO: 31)HO-Bc-B′t-Bg-B′u-B′t-Ba-Bg-Bc-Bc-Ba-Bc-B′t-Bg-Ba- B′t-B′t-Ba-Ba-CH₂CH₂OH(iii″-al a compound represented by the following formula (iii″-a):

(iii″-a) (SEQ ID NO: 32)HO-B′t-Bg-Ba-Bg-Ba-Ba-Ba-Bc-B′t-Bg-B′t-B′u-Bc-Ba- Bg-Bc-B′u-B′t-CH₂CH₂OH(iv″-a) a compound represented by the following formula (iv″-a):

(iv″-a) (SEQ ID NO: 33) HO-Bc-Ba-Bg-Bg-Ba-Ba-B′t-B′t-B′u-Bg-B′t-Bg-B′u-Bc-B′u-B′u-B′t-Bc-CH₂CH₂OH(v″-a) a compound represented by the following formula (v″-a):

(v″-a) (SEQ ID NO: 34) HO-Bg-B′t-Ba-B′u-B′t-B′t-Ba-Bg-Bc-Ba-B′t-Bg-B′u-B′t-Bc-Bc-Bc-Ba-CH₂CH₂OH(vi″-a) a compound represented by the following formula (vi″-a):

(vi″-a) (SEQ ID NO: 35)HO-Ba-Bg-Bc-Ba-B′t-Bg-B′t-B′t-Bc-Bc-Bc-Ba-Ba-B′t- B′u-Bc-B′t-Bc-CH₂CH₂OH(vii″-a) a compound represented by the following formula (vii″-a):

(vii″-a) (SEQ ID NO: 36) HO-Bg-Bc-Bc-Bg-Bc-Bc-Ba-M-Uu-Uu-Bc-Uu-Bc-Ba-Ba-Bc-Ba-Bg-CH₂CH₂OH(viii″-a) a compound represented by the following formula (viii″-a):

(viii″-a) (SEQ ID NO: 37) HO-Bc-Ba-B′t-Ba-Ba-B′t-Bg-Ba-Ba-Ba-BaBc-Bg-Bc-Bc-Bg-Bc-Bc-CH₂CH₂OH(ix″-a) a compound represented by the following formula (ix″-a):

(ix″-a) (SEQ ID NO: 38) HO-B′t-B′u-Bc-Bc-Bc-Ba-Ba-B′t-B′u-Bc-B′t-Bc-Ba-Bg-Bg-Ba-Ba-B′t-CH₂CH₂OH(x″-a) a compound represented by the following formula (x″-a):

(x″-a) (SEQ ID NO: 39) HO-Bc-Bc-Ba-B′u-B′t-B′u-Bg-B′t-Ba-B′u-B′t-B′t-Ba-Bg-Bc-Ba-B′t-Bg-CH₂CH₂OH(xi″-a) a compound represented by the following formula (xi″-a):

(xi″-a) (SEQ ID NO: 40) HO-Bc-B′t-Bc-Ba-Bg-Ba-B′t-Bc-B′u-B′u-Bc-B′t-Ba-Ba-Bc-B′u-B′u-Bc-CH₂CH₂OH(xii″-a) a compound represented by the following formula (xii″-a):

(xii″-a) (SEQ ID NO: 41)HO-Ba-Bc-Bc-Bg-Bc-Bc-B′t-B′u-Bc-Bc-Ba-Bc-B′t-Bc- Ba-Bg-Ba-Bg-CH₂CH₂OH(xiii″-a) a compound represented by the following formula (xiii″-a):

(xiii″-a) (SEQ ID NO: 42) HO-B′t-Bc-B′t-B′t-Bg-Ba-Ba-Bg-B′t-Ba-Ba-Ba-Bc-Bg-Bg-B′t-B′u-B′t-CH₂CH₂OH(xiv″-a) a compound represented by the following formula (xiv″-a):

(xiv″-a) (SEQ ID NO: 43) HO-Bg-Bg-Bc-B′t-Bg-Bc-B′t-B′t-B′u-Bg-Bc-Bc-Bc-B′t-Bc-Ba-Bg-Bc-CH₂CH₂OH(xv″-a) a compound represented by the following formula (xv″-a):

(xv″-a) (SEQ ID NO: 44) HO-Ba-Bg-B′t-Bc-Bc-Ba-Bg-Bg-Ba-Bg-Bc-B′t-Ba-Bg-Bg-B′t-Bc-Ba-CH₂CH₂OH(xvi″-a) a compound represented by the following formula (xvi″-a):

(xvi″-a) (SEQ ID NO: 45)HO-Bg-Bc-B′t-Bc-Bc-Ba-Ba-B′t-Ba-Bg-B′t-Bg-Bg-B′t- Bc-Ba-Bg-B′t-CH₂CH₂OH(xvii″-a) a compound represented by the following formula (xvii″-a):

(xvii″-a) (SEQ ID NO: 46)HO-Bg-Bc-B′t-Ba-Bg-Bg-B′t-Bc-Ba-Bg-Bg-Bc-B′t-Bg- Bc-B′t-B′t-B′u-CH₂CH₂OH(xviii″-a) a compound represented by the following formula (xviii″-a):

(xviii″-a) (SEQ ID NO: 47)HO-Bg-Bc-Ba-Bg-Bc-Bc-B′u-Bc-B′t-Bc-Bg-Bc-B′t-Bc- Ba-Bc-B′t-Bc-CH₂CH₂OH(xix″-a) a compound represented by the following formula (xix″-a):

(xix″-a) (SEQ ID NO: 48)HO-B′t-Bc-B′u-B′u-Bc-Bc-Ba-Ba-Ba-Bg-Bc-Ba-Bg-Bc- Bc-B′u-Bc-B′t-CH₂CH₂OH(xx″-a) a compound represented by the following formula (xx″-a):

(xx″-a) (SEQ ID NO: 49) HO-B′t-Bg-Bc-Ba-Bg-B′t-Ba-Ba-B′t-Bc-B′u-Ba-B′t-Bg-Ba-Bg-B′t-B′t-CH₂CH₂OH(xxi″-a) a compound represented by the following formula (xxi″-a):

(xxi″-a) (SEQ ID NO: 50)HO-Bg-B′t-B′t-B′u-Bc-Ba-Bg-Bc-B′u-B′t-Bc-B′t-Bg-B′t-Ba-Ba-Bg-Bc-CH₂CH₂OH(xxii″-a) a compound represented by the following formula (xxii″-a):

(xxii″-a) (SEQ ID NO: 51)HO-B′t-Bg-B′t-Ba-Bg-Bg-Ba-Bc-Ba-B′t-B′t-Bg-Bg-Bc- Ba-Bg-B′t-B′t-CH₂CH₂OH(xxiii″-a) a compound represented by the following formula (xxiii″-a):

(xxiii″-a) (SEQ ID NO: 52)HO-B′t-Bc-Bc-B′t-B′t-Ba-Bc-Bg-Bg-Bg-B′t-Ba-Bg-Bc- Ba-B′u-Bc-Bc-CH₂CH₂OH(xxiv″-a) a compound represented by the following formula (xxiv″-a):

(xxiv″-a) (SEQ ID NO: 53)HO-Ba-Bg-Bc-B′t-Bc-B′u-B′t-B′u-B′t-Ba-Bc-B′t-Bc-Bc-Bc-B′t-B′t-Bg-CH₂CH₂OH(xxv″-a) a compound represented by the following formula (xxv″-a):

(xxv″-a) (SEQ ID NO: 54)HO-Bc-Bc-Ba-B′u-B′t-Bg-B′u-B′t-B′u-Bc-Ba-B′u-Bc-Ba-Bg-Bc-B′t-Bc-CH₂CH₂OH(xxvi″-a) a compound represented by the following formula (xxvi″-a):

(xxvi″-a) (SEQ ID NO: 55)HO-Bc-B′t-Ba-B′t-Bg-Ba-Bg-B′t-B′t-B′t-Bc-B′t-B′t-Bc-Bc-Ba-Ba-Ba-CH₂CH₂OH(xxvii″-a) a compound represented by the following formula (xxvii″-a):

(xxvii″-a) (SEQ ID NO: 56)D-B′t-Bg-B′t-Bg-B′t-Bc-Ba-Bc-Bc-Ba-Bg-Ba-Bg-B′u-Ba-Ba-Bc-Ba-Bg-B′t-CH₂CH₂OH(xxviii″-a) a compound represented by the following formula (xxviii″-a):

(xxviii″-a) (SEQ ID NO: 57)D-Ba-Bg-Bg-B′t-B′t-Bg-B′u-Bg-B′u-Bc-Ba-Bc-Bc-Ba-Bg-Ba-Bg-B′t-Ba-Ba-CH₂CH₂OH(xxix″-a) a compound represented by the following formula (xxix″-a):

(xxix″-a) (SEQ ID NO: 58)D-Ba-Bg-B′t-Ba-Ba-Bc-Bc-Ba-Bc-Ba-Bg-Bg-B′u-B′u-Bg-B′t-Bg-B′t-Bc-Ba-CH₂CH₂OH(xxx″-a) a compound represented by the following formula (xxx″-a):

(xxx″-a) (SEQ ID NO: 59)D-B′t-B′t-Bg-Ba-B′t-Bc-Ba-Ba-Bg-Bc-Ba-Bg-Ba-Bg-Ba-Ba-Ba-Bg-Bc-Bc-CH₂CH₂OH(xxxi″-a) a compound represented by the following formula (xxxi″-a):

(xxxi″-a) (SEQ ID NO: 60)D-Bc-Ba-Bc-Bc-Bc-B′u-Bc-B′u-Bg-B′u-Bg-Ba-B′u-B′u-B′u-B′t-Ba-B′t-Ba-Ba-CH₂CH₂OH(xxxii″-a) a compound represented by the following formula (xxxii″-a):

(xxxii″-a) (SEQ ID NO: 61)D-Ba-Bc-Bc-Bc-Ba-Bc-Bc-Ba-B′u-Bc-Ba-Bc-Bc-Bc-B′u-Bc-B′t-Bg-B′t-Bg-CH₂CH₂OH(xxxiii″-a) a compound represented by the following formula (xxxiii″-a):

(xxxiii″-a) (SEQ ID NO: 62)D-Bc-Bc-B′t-Bc-Ba-Ba-Bg-Bg-B′u-Bc-Ba-Bc-Bc-Bc-Ba-Bc-Bc-Ba-B′t-Bc-CH₂CH₂OH(xxxiv″-a) a compound represented by the following formula (xxxiv″-a):

(xxxiv″-a) (SEQ ID NO: 63)HO-B′t-Ba-Ba-Bc-Ba-Bg-B′u-Bc-B′u-Bg-Ba-Bg-B′u- Ba-Bg-Bg-Ba-Bg-CH₂CH₂OH(xxxv″-a) a compound represented by the following formula (xxxv″-a):

(xxxv″-a) (SEQ ID NO: 64)HO-Bg-Bg-Bc-Ba-B′t-B′u-B′u-Bc-B′u-Ba-Bg-B′u-B′u-B′t-Bg-Bg-Ba-Bg-CH₂CH₂OH(xxxvi″-a) a compound represented by the following formula (xxxvi″-a):

(xxxvi″-a) (SEQ ID NO: 65)HO-Ba-Bg-Bc-Bc-Ba-Bg-B′u-Bc-Bg-Bg-B′u-Ba-Ba-Bg- B′t-B′t-Bc-B′t-CH₂CH₂OH(xxxvii″-a) a compound represented by the following formula (xxxvii″-a):

(xxxvii″-a) (SEQ ID NO: 66)HO-Ba-Bg-B′t-B′t-B′t-Bg-Bg-Ba-Bg-Ba-B′u-Bg-Bg- Bc-Ba-Bg-B′t-B′t-CH₂CH₂OH(xxxviii″-a) a compound represented by the following formula(xxxviii″-a):

(xxxviii″-a) (SEQ ID NO: 67)HO-Bc-B′t-Bg-Ba-B′t-B′t-Bc-B′t-Bg-Ba-Ba-B′t-B′t-Bc-B′u-B′u-B′t-Bc-CH₂CH₂OH(xxxix″-a) a compound represented by the following formula (xxxix″-a):

(xxxix″-a) (SEQ ID NO: 68)HO-B′t-B′t-Bc-B′t-B′t-Bg-B′t-Ba-Bc-B′t-B′t-Bc-Ba-B′t-Bc-Bc-Bc-Ba-CH₂CH₂OH(xl″-a) a compound represented by the following formula (xl″-a):

(xl″-a) (SEQ ID NO: 187) HO-Bc-Bc-B′t-Bc-Bc-Bg-Bg-B′t-B′t-Bc-B′t-Bg-Ba-Ba-Bg-Bg-B′t-Bg-CH₂CH₂OH(xli″-a) a compound represented by the following formula (xli″-a):

(xli″-a) (SEQ ID NO: 195)HO-Bc-Ba-B′t-B′t-B′t-Bc-Ba-B′u-B′t-Bc-Ba-Ba-Bc-B′t-Bg-B′t-B′t-Bg-CH₂CH₂OH(xlii″-a) a compound represented by the following formula (xlii″-a):

(xlii″-a) (SEQ ID NO: 71)HO-B′t-B′t-Bc-Bc-B′t-B′t-Ba-Bg-Bc-B′t-B′u-Bc-Bc- Ba-Bg-Bc-Bc-Ba-CH₂CH₂OH(xliii″-a) a compound represented by the following formula (xliii″-a):

(xliii″-a) (SEQ ID NO: 72)HO-B′t-Ba-Ba-Bg-Ba-Bc-Bc-B′t-Bg-Bc-B′t-Bc-Ba-Bg- Bc-B′u-B′t-Bc-CH₂CH₂OH(xliv″-a) a compound represented by the following formula (xliv″-a):

(xliv″-a) (SEQ ID NO: 73) HO-Bc-B′t-B′t-Bg-Bg-Bc-B′t-Bc-B′t-Bg-Bg-Bc-Bc-B′t-Bg-B′u-Bc-Bc-CH₂CH₂OH(xlv″-a) a compound represented by the following formula (xlv″-a):

(xlv″-a) (SEQ ID NO: 74) HO-Bc-B′t-Bc-Bc-B′t-B′u-Bc-Bc-Ba-B′t-Bg-Ba-Bc-B′t-Bc-Ba-Ba-Bg-CH₂CH₂OH(xlvi″-a) a compound represented by the following formula (xlvi″-a):

(xlvi″-a) (SEQ ID NO: 75)HO-Bc-B′t-Bg-Ba-Ba-Bg-Bg-B′t-Bg-B′t-B′t-Bc-B′t-B′t-Bg-B′t-Ba-Bc-CH₂CH₂OH(xlvii″-a) a compound represented by the following formula (xlvii″-a):

(xlvii″-a) (SEQ ID NO: 76)HO-B′t-B′t-Bc-Bc-Ba-Bg-Bc-Bc-Ba-B′t-B′t-Bg-B′t-Bg-B′t-B′t-Bg-Ba-CH₂CH₂OH(xlviii″-a) a compound represented by the following formula (xlviii″-a):

(xlviii″-a) (SEQ ID NO: 77)HO-Bc-B′t-Bc-Ba-Bg-Bc-B′t-B′u-Bc-B′t-B′t-Bc-Bc-B′t-B′t-Ba-Bg-Bc-CH₂CH₂OH(xlix″-a) a compound represented by the following formula (xlix″-a):

(xlix″-a) (SEQ ID NO: 78)HO-Bg-Bc-B′t-B′t-Bc-B′u-B′t-Bc-Bc-B′u-B′t-Ba-Bg-Bc-B′u-B′t-Bc-Bc-CH₂CH₂OH(l″-a) a compound represented by the following formula (l″-a):

(l″-a) (SEQ ID NO: 87) HO-Bg-Bg-Bc-Ba-B′t-B′t-B′u-Bc-B′t-Ba-Bg-B′u-B′t-B′t-Bg-Bg-Ba-Bg-CH₂CH₂OH(li″-a) a compound represented by the following formula (li″-a):

(li″-a) (SEQ ID NO: 88)HO-Ba-Bg-B′t-B′u-B′t-Bg-Bg-Ba-Bg-Ba-B′t-Bg-Bg-Bc- Ba-Bg-B′t-B′t-CH₂CH₂OHwhere Bg is a group represented by the following formula (G1) or (G2);Ba is a group represented by the following formula (A1) or (A2); Bc is agroup represented by the following formula (C1) or (C2); B′t is a grouprepresented by the following formula (T2); B′u is a formula representedby the following formula (U1); and D is HO— or Ph- wherein Ph- is agroup represented by the following first formula:

where X is individually and independently a group represented by thefollowing formula (X1) or (X2):

Y is individually and independently a hydrogen atom, a hydroxyl group oran alkoxy group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms.[49] The compound of any one of [26] to [48] above which is representedby any one of the following formulas (I″1) to (I″51), or apharmacologically acceptable salt thereof:

(I″1) (SEQ ID NO: 30) HO-Bg*-Ba**-Ba*-Ba*-Ba*-Bc**-Bg*-Bc**-Bc**-Bg*-Bc*-Bc**-Ba*-Bt**-Bu*-Bu*-Bc**-Bt**-CH₂CH₂OH (I″2) (SEQ ID NO: 31)HO-Bc**-Bt**-Bg*-Bu*-Bt**-Ba*-Bg*-Bc**-Bc*-Ba*-Bc**-Bt**-Bg*-Ba*-Bt**-Bt**-Ba*-Ba*-CH₂CH₂OH (I″3) (SEQ ID NO: 32)HO-Bt**-Bg*-Ba*-Bg*-Ba**-Ba*-Ba*-Bc**-Bt**-Bg*-Bt**-Bu*-Bc**-Ba*-Bg*-Bc**-Bu*-Bt**-CH₂CH₂OH (I″4) (SEQ ID NO: 33)HO-Bc**-Ba*-Bg*-Bg*-Ba**-Ba*-Bt**-Bt**-Bu*-Bg*-Bt**-Bg*-Bu*-Bc**-Bu*-Bu*-Bt**-Bc**-CH₂CH₂OH (I″5) (SEQ ID NO: 34)HO-Bg*-Bt**-Ba*-Bu*-Bt**-Bt**-Ba*-Bg*-Bc**-Ba*-Bt**-Bg*-Bu*-Bt**-Bc*-Bc**-Bc**-Ba*-CH₂CH₂OH (I″6) (SEQ ID NO: 35)HO-Ba*-Bg*-Bc**-Ba*-Bt**-Bg*-Bt**-Bt**-Bc*-Bc*-Bc**-Ba*-Ba*-Bt**-Bu*-Bc*-Bt**-Bc**-CH₂CH₂OH (I″7) (SEQ ID NO: 36)HO-Bg*-Bc**-Bc**-Bg*-Bc**-Bc*-Ba*-Bt**-Bu*-Bu*-Bc**-Bu*-Bc**-Ba*-Ba*-Bc**-Ba**-Bg*-CH₂CH₂OH (I″8) (SEQ ID NO: 37)HO-Bc**-Ba*-Bt**-Ba*-Ba*-Bt**-Bg*-Ba*-Ba**-Ba*-Ba*-Bc**-Bg*-Bc*-Bc**-Bg*-Bc**-Bc**-CH₂CH₂OH (I″9) (SEQ ID NO: 38)HO-Bt**-Bu*-Bc**-Bc*-Bc**-Ba*-Ba*-Bt**-Bu*-Bc*-Bt**-Bc**-Ba*-Bg*-Bg*-Ba**-Ba*-Bt**-CH₂CH₂OH (I″10) (SEQ ID NO: 39)HO-Bc**-Bc**-Ba*-Bu*-Bt**-Bu*-Bg*-Bt**-Ba*-Bu*-Bt**-Bt**-Ba*-Bg*-Bc**-Ba*-Bt**-Bg*-CH₂CH₂OH (I″11) (SEQ ID NO: 40)HO-Bc*-Bt**-Bc**-Ba*-Bg*-Ba*-Bt**-Bc**-Bu*-Bu*-Bc**-Bt**-Ba*-Ba*-Bc**-Bu*-Bu*-Bc**-CH₂CH₂OH (I″12) (SEQ ID NO: 41)HO-Ba*-Bc**-Bc**-Bg*-Bc*-Bc**-Bt**-Bu*-Bc*-Bc**-Ba*-Bc*-Bt**-Bc**-Ba*-Bg*-Ba**-Bg*-CH₂CH₂OH (I″13) (SEQ ID NO: 42)HO-Bt**-Bc*-Bt**-Bt**-Bg*-Ba*-Ba*-Bg*-Bt**-Ba*-Ba**-Ba*-Bc**-Bg*-Bg*-Bt**-Bu*-Bt**-CH₂CH₂OH (I″14) (SEQ ID NO: 43)HO-Bg*-Bg*-Bc**-Bt**-Bg*-Bc*-Bt**-Bt**-Bu*-Bg*-Bc**-Bc*-Bc*-Bt**-Bc**-Ba*-Bg*-Bc**-CH₂CH₂OH (I″15) (SEQ ID NO: 44)HO-Ba*-Bg*-Bt**-Bc**-Bc**-Ba*-Bg*-Bg*-Ba**-Bg*-Bc**-Bt**-Ba*-Bg*-Bg*-Bt**-Bc**-Ba*-CH₂CH₂OH (I″16) (SEQ ID NO: 45)HO-Bg*-Bc**-Bt**-Bc*-Bc**-Ba*-Ba*-Bt**-Ba*-Bg*-Bt**-Bg*-Bg*-Bt**-Bc**-Ba*-Bg*-Bt**-CH₂CH₂OH (I″17) (SEQ ID NO: 46)HO-Bg*-Bc**-Bt**-Ba*-Bg*-Bg*-Bt**-Bc**-Ba*-Bg*-Bg*-Bc**-Bt**-Bg*-Bc*-Bt**-Bt**-Bu*-CH₂CH₂OH (I″18) (SEQ ID NO: 47)HO-Bg*-Bc**-Ba*-Bg*-Bc**-Bc**-Bu*-Bc*-Bt**-Bc*-Bg*-Bc**-Bt**-Bc*-Ba*-Bc**-Bt**-Bc*-CH₂CH₂OH (I″19) (SEQ ID NO: 48)HO-Bt**-Bc**-Bu*-Bu*-Bc**-Bc**-Ba*-Ba*-Ba*-Bg*-Bc**-Ba*-Bg*-Bc**-Bc*-Bu*-Bc**-Bt**-CH₂CH₂OH (I″20) (SEQ ID NO: 49)HO-Bt**-Bg*-Bc**-Ba*-Bg*-Bt**-Ba*-Ba*-Bt**-Bc**-Bu*-Ba*-Bt**-Bg*-Ba*-Bg*-Bt**-Bt**-CH₂CH₂OH (I″21) (SEQ ID NO: 50)HO-Bg*-Bt**-Bt**-Bu*-Bc**-Ba*-Bg*-Bc**-Bu*-Bt**-Bc*-Bt**-Bg*-Bt**-Ba*-Ba*-Bg*-Bc**-CH₂CH₂OH (I″22) (SEQ ID NO: 51)HO-Bt**-Bg*-Bt**-Ba*-Bg*-Bg*-Ba*-Bc**-Ba*-Bt**-Bt**-Bg*-Bg*-Bc**-Ba*-Bg*-Bt**-Bt**-CH₂CH₂OH (I″23) (SEQ ID NO: 52)HO-Bt**-Bc*-Bc*-Bt**-Bt**-Ba*-Bc**-Bg*-Bg*-Bg*-Bt**-Ba*-Bg*-Bc**-Ba*-Bu*-Bc**-Bc**-CH₂CH₂OH (I″24) (SEQ ID NO: 53)HO-Ba*-Bg*-Bc**-Bt**-Bc*-Bu*-Bt**-Bu*-Bt**-Ba*-Bc*-Bt**-Bc**-Bc*-Bc*-Bt**-Bt**-Bg*-CH₂CH₂OH (I″25) (SEQ ID NO: 54)HO-Bc**-Bc**-Ba*-Bu*-Bt**-Bg*-Bu*-Bt**-Bu*-Bc**-Ba*-Bu*-Bc**-Ba*-Bg*-Bc*-Bt**-Bc**-CH₂CH₂OH (I″26) (SEQ ID NO: 55)HO-Bc*-Bt**-Ba*-Bt**-Bg*-Ba*-Bg*-Bt**-Bt**-Bt**-Bc*-Bt**-Bt**-Bc*-Bc*-Ba*-Ba**-Ba*-CH₂CH₂OH (I″27) (SEQ ID NO: 56)Ph-Bt**-Bg**-Bt**-Bg**-Bt**-Bc*-Ba*-Bc*-Bc*-Ba*-Bg*-Ba*-Bg*-Bu*-Ba*-Ba**-Bc**-Ba**-Bg**-Bt**- CH₂CH₂OH (I″28) (SEQ IDNO: 57) Ph-Ba**-Bg**-Bg**-Bt**-Bt**-Bg*-Bu*-Bg*-Bu*-Bc*-Ba*-Bc*-Bc*-Ba*-Bg*-Ba**-Bg**-Bt**-Ba**-Ba**- CH₂CH₂OH (I″29) (SEQ IDNO: 58) Ph-Ba**-Bg**-Bt**-Ba**-Ba**-Bc*-Bc*-Ba*-Bc*-Ba*-Bg*-Bg*-Bu*-Bu*-Bg*-Bt**-Bg**-Bt**-Bc**-Ba**- CH₂CH₂OH (I″30) (SEQ IDNO: 59) Ph-Bt**-Bt**-Bg**-Ba**-Bt**-Bc*-Ba*-Ba*-Bg*-Bc*-Ba*-Bg*-Ba*-Bg*-Ba*-Ba**-Ba**-Bg**-Bc**-Bc**- CH₂CH₂OH (I″31) (SEQ IDNO: 60) Ph-Bc**-Ba**-Bc**-Bc**-Bc**-Bu*-Bc*-Bu*-Bg*-Bu*-Bg*-Ba*-Bu*-Bu*-Bu*-Bt**-Ba**-Bt**-Ba**-Ba**- CH₂CH₂OH (I″32) (SEQ IDNO: 61) Ph-Ba**-Bc**-Bc**-Bc**-Ba**-Bc*-Bc*-Ba*-Bu*-Bc*-Ba*-Bc*-Bc*-Bc*-Bu*-Bc**-Bt**-Bg**-Bt**-Bg**- CH₂CH₂OH (I″33) (SEQ IDNO: 62) Ph-Bc**-Bc**-Bt**-Bc**-Ba**-Ba*-Bg*-Bg*-Bu*-Bc*-Ba*-Bc*-Bc*-Bc*-Ba*-Bc**-Bc**-Ba**-Bt**-Bc**- CH₂CH₂OH (I″34) (SEQ IDNO: 63) HO-Bt**-Ba**-Ba**-Bc**-Ba**-Bg*-Bu*-Bc*-Bu*-Bg*-Ba*-Bg*-Bu*-Ba**-Bg**-Bg**-Ba**-Bg**-CH₂CH₂OH (I″35) (SEQ ID NO: 64)HO-Bg**-Bg**-Bc**-Ba**-Bt**-Bu*-Bu*-Bc*-Bu*-Ba*-Bg*-Bu*-Bu*-Bt**-Bg**-Bg**-Ba**-Bg**-CH₂CH₂OH (I″36) (SEQ ID NO: 65)HO-Ba**-Bg**-Bc**-Bc**-Ba**-Bg*-Bu*-Bc*-Bg*-Bg*-Bu*-Ba*-Ba*-Bg**-Bt**-Bt**-Bc**-Bt**-CH₂CH₂OH (I″37) (SEQ ID NO: 66)HO-Ba**-Bg**-Bt**-Bt**-Bt**-Bg*-Bg*-Ba*-Bg*-Ba*-Bu*-Bg*-Bg*-Bc**-Ba**-Bg**-Bt**-Bt**-CH₂CH₂OH (I″38) (SEQ ID NO: 67)HO-Bc**-Bt**-Bg*-Ba*-Bt**-Bt**-Bc*-Bt**-Bg*-Ba*-Ba*-Bt**-Bt**-Bc**-Bu*-Bu*-Bt**-Bc**-CH₂CH₂OH (I″39) (SEQ ID NO: 68)HO-Bt**-Bt**-Bc*-Bt**-Bt**-Bg*-Bt**-Ba*-Bc*-Bt**-Bt**-Bc*-Ba*-Bt**-Bc*-Bc**-Bc**-Ba*-CH₂CH₂OH (I″40) (SEQ ID NO: 69)HO-Bc**-Bc**-Bu*-Bc**-Bc**-Bg*-Bg*-Bt**-Bt**-Bc**-Bt**-Bg*-Ba*-Ba*-Bg*-Bg*-Bt**-Bg*-CH₂CH₂OH (I″41) (SEQ ID NO: 70)HO-Bc**-Ba*-Bt**-Bt**-Bu*-Bc**-Ba*-Bu*-Bt**-Bc**-Ba*-Ba*-Bc**-Bt**-Bg*-Bt**-Bt**-Bg*-CH₂CH₂OH (I″42) (SEQ ID NO: 71)HO-Bt**-Bt**-Bc*-Bc*-Bt**-Bt**-Ba*-Bg*-Bc**-Bt**-Bu*-Bc**-Bc**-Ba*-Bg*-Bc**-Bc**-Ba*-CH₂CH₂OH (I″43) (SEQ ID NO: 72)HO-Bt**-Ba*-Ba*-Bg*-Ba*-Bc**-Bc**-Bt**-Bg*-Bc**-Bt**-Bc**-Ba*-Bg*-Bc**-Bu*-Bt**-Bc**-CH₂CH₂OH (I″44) (SEQ ID NO: 73)HO-Bc**-Bt**-Bt**-Bg*-Bg*-Bc**-Bt**-Bc*-Bt**-Bg*-Bg*-Bc*-Bc**-Bt**-Bg*-Bu*-Bc**-Bc**-CH₂CH₂OH (I″45) (SEQ ID NO: 74)HO-Bc**-Bt**-Bc*-Bc**-Bt**-Bu*-Bc**-Bc**-Ba*-Bt**-Bg*-Ba*-Bc**-Bt**-Bc**-Ba*-Ba*-Bg*-CH₂CH₂OH (I″46) (SEQ ID NO: 75)HO-Bc**-Bt**-Bg*-Ba*-Ba*-Bg*-Bg*-Bt**-Bg*-Bt**-Bt**-Bc**-Bt**-Bt**-Bg*-Bt**-Ba*-Bc**-CH₂CH₂OH (I″47) (SEQ ID NO: 76)HO-Bt**-Bt**-Bc*-Bc**-Ba*-Bg*-Bc**-Bc**-Ba*-Bt**-Bt**-Bg*-Bt**-Bg*-Bt**-Bt**-Bg*-Ba*-CH₂CH₂OH (I″48) (SEQ ID NO: 77)HO-Bc**-Bt**-Bc**-Ba*-Bg*-Bc**-Bt**-Bu*-Bc*-Bt**-Bt**-Bc*-Bc*-Bt**-Bt**-Ba*-Bg*-Bc**-CH₂CH₂OH (I″49) (SEQ ID NO: 78)HO-Bg*-Bc**-Bt**-Bt**-Bc*-Bu*-Bt**-Bc**-Bc*-Bu*-Bt**-Ba*-Bg*-Bc**-Bu*-Bt**-Bc**-Bc**-CH₂CH₂OH (I″50) (SEQ ID NO: 87)HO-Bg*-Bg*-Bc**-Ba*-Bt**-Bt**-Bu*-Bc**-Bt**-Ba*-Bg*-Bu*-Bt**-Bt**-Bg*-Bg*-Ba**-Bg*-CH₂CH₂OH (I″51) (SEQ ID NO: 88)HO-Ba**-Bg*-Bt**-Bu*-Bt**-Bg*-Bg*-Ba**-Bg*-Ba*-Bt**-Bg*-Bg*-Bc**-Ba**-Bg*-Bt**-Bt**-CH₂CH₂OHwhere Bg* is a group represented by the following formula (G1^(a)), Ba*is a group represented by the following formula (A1^(a)); Bc* is a grouprepresented by the following formula (C1^(a)); Bu* is a grouprepresented by the following formula (U1^(a)); Bg** is a grouprepresented by the following formula (G2); Ba** is a group representedby the following formula (A2); Bc** is a group represented by thefollowing formula (C2); Bt** is a group represented by the followingformula (T2); and Ph- is a group represented by the following firstformula:

where X is individually and independently a group represented by thefollowing formula (X1) or (X2); R¹ is individually and independently analkyl group with 1-6 carbon atoms; and Z is individually andindependently a single bond or an alkylene group with 1-5 carbon atoms:

[50] The compound of [49] above where X in formulas (G1^(a)), (A1^(a)),(C1^(a)) and (U1^(a)) is a group represented by formula (X2) and X informulas (G2), (A2), (C2) and (T2) is a group represented by formula(X1), or a pharmacologically acceptable salt thereof.[51] The compound of [49] above where X in all the formulas (G1^(a)),(A1^(a)), (C1^(a)), (U1^(a)), (G2), (A2), (C2) and (T2) is a grouprepresented by formula (X2), or a pharmacologically acceptable saltthereof.[52] The compound of [49] above which is represented by any one of thefollowing formulas (I″50-a) to (I″51-b), or a salt thereof:

(1″50-a) (SEQ ID NO: 87)

(1″50-b) (SEQ ID NO: 87) HO-Bg*-Bg*-Bc**-Ba*-Bt**-Bt**-Bu*-Bc**-Bt**-Ba*-Bg*-Bu*-Bt**-Bt**-Bg*-Bg*-Ba**- Bg*-CH₂CH₂OH (I″49-a)(SEQ ID NO: 78) HO-Bg*-Bc**-Bt**-Bt**-Bc*-Bu*-Bt**-Bc**-BC*-Bu*-Bt**-Ba*-Bg*-Bc**-Bu*-Bt**-Bc**- Bc**-CH₂CH₂OH (I″1-a)(SEQ ID NO: 30) HO-Bg*-Ba**-Ba*-Ba*-Ba*-Bc**-Bg*-Bc**-Bc**-Bg*-Bc*-Bc**-Ba*-Bg**-Bu*-Bu*-Bc**- Bt**-CH₂CH₂OH (I″12-a)(SEQ ID NO: 41) HO-Ba*-Bc**-Bc**-Bg*-Bc*-Bc**-Bt**-Bu*-Bc*-Bc**-Ba*-Bc*-Bt**-Bc**-Ba**-Bg*-Ba**- Bg*-CH₂CH₂OH (I″18-a)(SEQ ID NO: 47) HO-Bg*-Bc**-Ba*-Bg*-Bc**-Bc**-Bu*-Bc*-Bt**-Bc*-Bg*-Bc**-Bt**-Bc*-Ba*-Bc**-Bt**- Bc*-CH₂CH₂OH (I″19-a)(SEQ ID NO: 48) HO-Bt**-Bc**-Bu*-Bu*-Bc**-Bc**-Ba*-Ba*-Ba*-Bg*-Bc**-Ba*-Bg*-Bc**-Bc*-Bu*-Bc**- Bt**-CH₂CH₂OH (I″51-a)(SEQ ID NO: 88) HO-Ba**-Bg*-Bt**-Bu*-Bt**-Bg*-Bg*-Ba**-Bg*-Ba*-Bt**-Bg*-Bg*-Bc**-Ba**-Bg*-Bt**- Bt**-CH₂CH₂OH (I″51-b)(SEQ ID NO: 88)

where Bg* is a group represented by formula (G1^(a)), Ba* is a grouprepresented by formula (A1^(a)); Bc* is a group represented by formula(C1^(a)); Bu* is a group represented by formula (U1^(a)); Bg** is agroup represented by formula (G2); Ba** is a group represented byformula (A2); Bc** is a group represented by formula (C2); Bt** is agroup represented by formula (T2); and in individual formulas, at leastone of Bg*, Ba*, Bc*, Bu*, Bg**, Ba**, Bc** and Bt** has a grouprepresented by formula (X2) as X and all of

,

,

,

,

,

,

and

have a group represented by formula (X1) as X.[53] The compound of any one of [26] to [52] above where Y in formulas(G1), (A1), (C1) and (U1) is a methoxy group and Z in formulas (G2),(A2), (C2) and (T2) is an ethylene group, or a pharmacologicallyacceptable salt thereof.[54] A therapeutic agent for muscular dystrophy, comprising theoligonucleotide of [1] above or a pharmacologically acceptable saltthereof, or the compound of any one of [6], [13] to [19] and [26] to[46] or a pharmacologically acceptable salt thereof.[55] The therapeutic agent of [54] above, which is an agent for treatingDuchenne muscular dystrophy.[56] The therapeutic agent of [54] above, whose target of treatment isthose patients in which the total number of the amino acids in the openreading frame of the dystrophin gene will be a multiple of 3 when exon19, 41, 45, 46, 44, 50, 55, 51 or 53 of the dystrophin gene has beenskipped.

The term “oligonucleotide” used in the present invention encompasses notonly oligo DNA or oligo RNA, but also an oligonucleotide in which atleast one D-ribofuranose constituting the oligonucleotide is2′-O-alkylated; an oligonucleotide in which at least one D-ribofuranoseconstituting the oligonucleotide is 2′-O,4′-C-alkylenated; anoligonucleotide in which at least one phosphate constituting theoligonucleotide is thioated; or a combination thereof. Sucholigonucleotides in which at least one D-ribofuranose constituting theoligonucleotides is 2′-O-alkylated or 2′-O,4′-C-alkylenated have highbinding strength to RNA and high resistance to nuclease. Thus, they areexpected to produce higher therapeutic effect than natural nucleotides(i.e. oligo DNA or oligo RNA). Further, an oligonucleotide in which atleast one phosphate constituting the oligonucleotide is thioated alsohas high resistance to nuclease and, thus, is expected to produce highertherapeutic effect than natural nucleotides (i.e. oligo DNA or oligoRNA). An oligonucleotide comprising both the modified sugar and themodified phosphate as described above has still higher resistance tonuclease and, thus, is expected to produce still higher therapeuticeffect.

With respect to the oligonucleotide of the present invention, examplesof the modification of sugar include, but are not limited to,2′-O-alkylation (e.g. 2′-O-methylation, 2′-O-aminoethylation,2′-O-propylation, 2′-O-allylation, 2′-O-methoxyethylation,2′-O-butylation, 2′-O-pentylation, or 2′-O-propargylation) ofD-ribofuranose; 2′-O,4′-C-alkylenation (e.g. 2′-O,4′-C-ethylenation,2′-O,4′-C-methylenation, 2′-O,4′-C-propylenation,2′-O,4′-C-tetramethylation, or 2′-O,4′-C-pentamethylation) ofD-ribofuranose; 3′-deoxy-3′-amino-2′-deoxy-D-ribofuranose; and3′-deoxy-3′-amino-2′-deoxy-2′-fluoro-D-ribofuranose.

With respect to the oligonucleotide of the present invention, examplesof the modification of phosphate include, but are not limited to,phosphorothioate, methylphosphonate, methylthiophosphonate,phosphorodithioate and phosphoroamidate.

With respect to Y in formulas (G1), (A1), (C1) and (U1), examples of thealkoxy group with 1-6 carbon atoms include, but are not limited to,methoxy group, aminoethoxy group, propoxy group, allyloxy group,methoxyethoxy group, butoxy group, pentyloxy group, and propargyloxygroup.

With respect to Z in formulas (G2), (A2), (C2) and (T2), examples of thealkylene group with 1-5 carbon atoms include, but are not limited to,methylene group, ethylene group, propylene group, tetramethylene groupand pentamethylene group.

With respect to R¹ in formulas (G1^(a)), (A1^(a)), (C1^(a)) and(U1^(a)), examples of the alkyl group with 1-6 carbon atoms include, butare not limited to, methyl group, aminoethyl group, propyl group, allylgroup, methoxyethyl group, butyl group, pentyl group and propargylgroup.

Preferable examples of the compound represented by general formula (I)include the following compounds.

(J-1) (SEQ ID NO: 196)HO-G^(e2p)-C^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-G^(mp)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-CH₂CH₂OH,(J-2) (SEQ ID NO: 197)HO-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH, (J-3) (SEQ ID NO: 198)HO-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-G^(mp)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-CH₂CH₂OH, (J-4) (SEQ ID NO: 199)HO-G^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-T^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-A^(mp)-G^(mp)-CH₂CH₂OH, (J-5) (SEQ ID NO: 200)HO-A^(mp)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(mp)-T^(e2p)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(e2p)-C^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH, (J-6) (SEQ ID NO: 201)HO-G^(e2p)-C^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(e2p)-C^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH, (J-7)(SEQ ID NO: 4)HO-A^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH, (J-8) (SEQ ID NO: 200)HO-A^(ms)-G^(e2s)-C^(e2s)-T^(e2s)-G^(e2s)-A^(ms)-T^(e2s)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(e2s)-C^(e2s)-A^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-CH₂CH₂OH, (J-9) (SEQ ID NO: 200)HO-A^(ms)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(ms)-T^(e2p)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(e2p)-C^(e2p)-A^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH, (J-10) (SEQ ID NO: 4)HO-A^(mp)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-G^(mp)-C^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH, (J-11) (SEQ ID NO: 4)HO-A^(ms)-G^(ms)-C^(e2s)-T^(e2s)-G^(ms)-A^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-G^(ms)-G^(ms)-C^(e2s)-A^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-CH₂CH₂OH, (J-12) (SEQ ID NO: 4)HO-A^(ms)-G^(ms)-C^(e2p)-T^(e2p)-G^(ms)-A^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-G^(ms)-C^(e2p)-T^(e2p)-G^(ms)-G^(ms)-C^(e2p)-A^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH, (J-13) (SEQ ID NO: 196)HO-G^(e1p)-C^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-A^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-G^(mp)-C^(e1p)-A^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-CH₂CH₂OH,(J-14) (SEQ ID NO: 197)HO-G^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-CH₂CH₂OH, (J-15) (SEQ ID NO: 198)HO-G^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-G^(mp)-C^(e1p)-A^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-CH₂CH₂OH, (J-16) (SEQ IDNO: 198)HO-G^(e1p)-A^(mp)-T^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-T^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-A^(mp)-G^(mp)-CH₂CH₂OH, (J-17) (SEQ ID NO: 200)HO-A^(mp)-G^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-A^(mp)-T^(e1p)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(e1p)-C^(e1p)-A^(mp)-T^(e1p)-C^(e1p)-T^(e1p)-CH₂CH₂OH, (J-18) (SEQ ID NO: 201)HO-G^(e1p)-C^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-A^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(e1p)-C^(e1p)-A^(mp)-T^(e1p)-C^(e1p)-T^(e1p)-CH₂CH₂OH,(J-19) (SEQ ID NO: 4)HO-A^(e1p)-G^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-G^(e1p)-C^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-CH₂CH₂OH, (J-20) (SEQ ID NO: 200)HO-A^(ms)-G^(e1s)-C^(e1s)-T^(e1s)-G^(e1s)-A^(ms)-T^(e1s)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(e1s)-C^(e1s)-A^(ms)-T^(e1s)-C^(e1s)-T^(e1s)-CH₂CH₂OH, (J-21) (SEQ ID NO: 200)HO-A^(ms)-G^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-A^(ms)-T^(e1p)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(e1p)-C^(e1p)-A^(ms)-T^(e1p)-C^(e1p)-T^(e1p)-CH₂CH₂OH, (J-22) (SEQ ID NO: 4)HO-A^(mp)-G^(mp)-C^(e1p)-T^(e1p)-G^(mp)-A^(mp)-T^(e1p)-C^(e1p)-T^(e1p)-G^(mp)-C^(e1p)-T^(e1p)-G^(mp)-G^(mp)-C^(e1p)-A^(mp)-T^(e1p)-C^(e1p)-T^(e1p)-CH₂CH₂OH, (J-23) (SEQ ID NO: 4)HO-A^(ms)-G^(ms)-C^(e1s)-T^(e1s)-G^(ms)-A^(ms)-T^(e1s)-C^(e1s)-T^(e1s)-G^(ms)-C^(e1s)-T^(e1s)-G^(ms)-G^(ms)-C^(e1s)-A^(ms)-T^(e1s)-C^(e1s)-T^(e1s)-CH₂CH₂OH, (J-24) (SEQ ID NO: 4)HO-A^(ms)-G^(ms)-C^(e1p)-T^(e1p)-G^(ms)-A^(ms)-T^(e1p)-C^(e1p)-T^(e1p)-G^(ms)-C^(e1p)-T^(e1p)-G^(ms)-G^(ms)-C^(e1p)-A^(ms)-T^(e1p)-C^(e1p)-T^(e1p)-CH₂CH₂OH, (J-25) (SEQ ID NO: 196)HO-G^(e2p)-C^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-G^(mp)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-CH₂CH₂CH₂OH,(J-26) (SEQ ID NO: 197)HO-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂CH₂OH, (J-27) (SEQ ID NO: 198)HO-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-G^(mp)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-CH₂CH₂CH₂OH, (J-28) (SEQID NO: 199)HO-G^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-T^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-A^(mp)-G^(mp)-CH₂CH₂CH₂OH, (J-29) (SEQ ID NO: 200)HO-A^(mp)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(mp)-T^(e2p)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(e2p)-C^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂CH₂OH, (J-30) (SEQ ID NO: 201)HO-G^(e2p)-C^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(e2p)-C^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂CH₂OH,(J-31) (SEQ ID NO: 4)HO-A^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂CH₂OH, (J-32) (SEQ ID NO: 200)HO-A^(ms)-G^(e2s)-C^(e2s)-T^(e2s)-G^(e2s)-A^(ms)-T^(e2s)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(e2s)-C^(e2s)-A^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-CH₂CH₂CH₂OH, (J-33) (SEQ ID NO: 200)HO-A^(ms)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(ms)-T^(e2p)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(e2p)-C^(e2p)-A^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂CH₂OH, (J-34) (SEQ ID NO: 4)HO-A^(mp)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-G^(mp)-C^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂CH₂OH, (J-35) (SEQ ID NO: 4)HO-A^(ms)-G^(ms)-C^(e2s)-T^(e2s)-G^(ms)-A^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-G^(ms)-G^(ms)-C^(e2s)-A^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-CH₂CH₂CH₂OH, (J-36) (SEQ ID NO: 4)HO-A^(ms)-G^(ms)-C^(e2p)-T^(e2p)-G^(ms)-A^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-G^(ms)-C^(e2p)-T^(e2p)-G^(ms)-G^(ms)-C^(e2p)-A^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂CH₂OH, (J-37) (SEQ ID NO: 200)HO-A^(mp)-G^(e1p)-C^(e2p)-T^(e2p)-G^(e1p)-A^(mp)-T^(e2p)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(e1p)-C^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH, (J-38) (SEQ ID NO: 200)HO-A^(ms)-G^(e1s)-C^(e2s)-T^(e2s)-G^(e1s)-A^(ms)-T^(e2s)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(e1s)-C^(e2s)-A^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-CH₂CH₂OH, (J-39) (SEQ ID NO: 200)HO-A^(ms)-G^(e1p)-C^(e2p)-T^(e2p)-G^(e1p)-A^(ms)-T^(e2p)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(e1p)-C^(e2p)-A^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH, (J-40) (SEQ ID NO: 4)HO-A^(mp)-G^(mp)-C^(e1p)-T^(e2p)-G^(mp)-A^(mp)-T^(e2p)-C^(e1p)-T^(e2p)-G^(mp)-C^(e1p)-T^(e2p)-G^(mp)-G^(mp)-C^(e2p)-A^(mp)-T^(e2p)-C^(e1p)-T^(e2p)-CH₂CH₂OH, (J-41) (SEQ ID NO: 4)HO-A^(ms)-G^(ms)-C^(e1s)-T^(e2s)-G^(ms)-A^(ms)-T^(e2s)-C^(e1s)-T^(e2s)-G^(ms)-C^(e1s)-T^(e2s)-G^(ms)-G^(ms)-C^(e2s)-A^(ms)-T^(e2s)-C^(e1s)-T^(e2s)-CH₂CH₂OH, (J-42) (SEQ ID NO: 4)HO-A^(ms)-G^(ms)-C^(e1p)-T^(e2p)-G^(ms)-A^(ms)-T^(e2p)-C^(e1p)-T^(e2p)-G^(ms)-C^(e1p)-T^(e2p)-G^(ms)-G^(ms)-C^(e1p)-A^(ms)-T^(e2p)-C^(e1p)-T^(e2p)-CH₂CH₂OH, (J-43) (SEQ ID NO: 4)HO-A^(mp)-G^(mp)-C^(mp)-T^(e2p)-G^(mp)-A^(mp)-T^(e2p)-C^(mp)-T^(e2p)-G^(mp)-C^(mp)-T^(e2p)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-T^(e2p)-C^(mp)-T^(e2p)-CH₂CH₂OH, (J-44) (SEQ ID NO: 4)HO-A^(ms)-G^(ms)-C^(ms)-T^(e2s)-G^(ms)-A^(ms)-T^(e2s)-C^(ms)-T^(e2s)-G^(ms)-C^(ms)-T^(e2s)-G^(ms)-G^(ms)-C^(ms)-A^(ms)-T^(e2s)-C^(ms)-T^(e2s)-CH₂CH₂OH, (J-45) (SEQ ID NO: 4)HO-A^(ms)-G^(ms)-C^(ms)-T^(e2p)-G^(ms)-A^(ms)-T^(e2p)-C^(ms)-T^(e2p)-G^(ms)-C^(ms)-T^(e2p)-G^(ms)-G^(ms)-C^(ms)-A^(ms)-T^(e2p)-C^(ms)-T^(e2p)-CH₂CH₂OH (J-46) (SEQ ID NO: 202)HO-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(e2p)-T^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-CH₂CH₂OH (J-47) (SEQ ID NO: 197)HO-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-U^(e2p)-G^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH (J-48) (SEQ ID NO: 202)HO-G^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(e1p)-T^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-CH₂CH₂OH (J-49) (SEQ ID NO: 197)HO-G^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-U^(e1p)-G^(e1p)-G^(e1p)-C^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-CH₂CH₂OH (J-50) (SEQ ID NO: 202)HO-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(ms)-C^(ms)-A^(ms)-U^(ms)-C^(e2p)-T^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-CH₂CH₂OH (J-51) (SEQ ID NO: 197)HO-G^(e2s)-A^(e2s)-T^(e2s)-C^(e2s)-T^(e2s)-G^(e2s)-C^(e2s)-U^(e2s)-G^(e2s)-G^(e2s)-C^(e2s)-A^(e2s)-T^(e2s)-C^(e2s)-T^(e2s)-CH₂CH₂OH (J-52) (SEQ ID NO: 202)HO-G^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(ms)-C^(ms)-A^(ms)-U^(ms)-C^(e1p)-T^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-CH₂CH₂OH (J-53) (SEQ ID NO: 197)HO-G^(e1s)-A^(e1s)-T^(e1s)-C^(e1s)-T^(e1s)-G^(e1s)-C^(e1s)-U^(e1s)-G^(e1s)-G^(e1s)-C^(e1s)-A^(e1s)-T^(e1s)-C^(e1s)-T^(e1s)-CH₂CH₂OH (J-54) (SEQ ID NO: 202)HO-G^(e2s)-A^(e2s)-T^(e2s)-C^(e2s)-T^(e2s)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(ms)-C^(ms)-A^(ms)-U^(ms)-C^(e2s)-T^(e2s)-T^(e2s)-G^(e2s)-C^(e2s)-CH₂CH₂OHEspecially preferable are (J-1) to (J-24) and (J-46) to (J-47).

Preferable examples of the compound represented by general formula (I′)include the following compounds.

(J-1) (SEQ ID NO: 203)HO-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(e2p)-A^(mp)-G^(mp)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-C^(mp)-G^(mp)-A^(mp)-A^(mp)-A^(mp)-C^(mp)-U^(mp)-G^(e2p)-A^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-CH₂CH₂OH (J-2) (SEQ ID NO: 204)HO-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-C^(mp)-U^(mp)-U^(mp)-C^(mp)-G^(mp)-A^(mp)-A^(mp)-A^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-CH₂CH₂OH (J-3) (SEQ ID NO: 205)HO-A^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-G^(mp)-C^(mp)-A^(mp)-A^(mp)-A^(mp)-U^(mp)-T^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH (J-4) (SEQ ID NO: 203)HO-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(e2p)-A^(ms)-G^(ms)-U^(ms)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-G^(ms)-A^(ms)-A^(ms)-A^(ms)-C^(ms)-U^(ms)-G^(e2p)-A^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-CH₂CH₂OH (J-5) (SEQ ID NO: 204)HO-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-G^(ms)-A^(ms)-A^(ms)-A^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-CH₂CH₂OH (J-6) (SEQ ID NO: 205)HO-A^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-T^(e2p)-G^(ms)-A^(ms)-G^(ms)-C^(ms)-A^(ms)-A^(ms)-A^(ms)-U^(ms)-T^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH (J-7) (SEQ ID NO: 203)HO-A^(e2s)-G^(e2s)-T^(e2s)-T^(e2s)-G^(e2s)-A^(ms)-G^(ms)-U^(ms)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-G^(ms)-A^(ms)-A^(ms)-A^(ms)-C^(ms)-U^(ms)-G^(e2s)-A^(e2s)-G^(e2s)-C^(e2s)-A^(e2s)-CH₂CH₂OH (J-8) (SEQ ID NO: 204)HO-A^(e2s)-G^(e2s)-T^(e2s)-T^(e2s)-G^(e2s)-A^(e2s)-G^(e2s)-T^(e2s)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-G^(ms)-A^(ms)-A^(ms)-A^(e2s)-C^(e2s)-T^(e2s)-G^(e2s)-A^(e2s)-G^(e2s)-C^(e2s)-A^(e2s)-CH₂CH₂OH (J-9) (SEQ ID NO: 205)HO-A^(e2s)-A^(e2s)-A^(e2s)-C^(e2s)-T^(e2s)-G^(ms)-A^(ms)-G^(ms)-C^(ms)-A^(ms)-A^(ms)-A^(ms)-U^(ms)-T^(e2s)-T^(e2s)-G^(e2s)-C^(e2s)-T^(e2s)-CH₂CH₂OH (J-10) (SEQ ID NO: 203)HO-A^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-G^(e1p)-A^(mp)-G^(mp)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-C^(mp)-G^(mp)-A^(mp)-A^(mp)-A^(mp)-C^(mp)-U^(mp)-G^(e1p)-A^(e1p)-G^(e1p)-C^(e1p)-A^(e1p)-CH₂CH₂OH (J-11) (SEQ ID NO: 204)HO-A^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-G^(e1p)-A^(e1p)-G^(e1p)-T^(e1p)-C^(mp)-U^(mp)-U^(mp)-C^(mp)-G^(mp)-A^(mp)-A^(mp)-A^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-A^(e1p)-G^(e1p)-C^(e1p)-A^(e1p)-CH₂CH₂OH (J-12) (SEQ ID NO: 205)HO-A^(e1p)-A^(e1p)-A^(e1p)-C^(e1p)-T^(e1p)-G^(mp)-A^(mp)-G^(mp)-C^(mp)-A^(mp)-A^(mp)-A^(mp)-U^(mp)-T^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-T^(e1p)-CH₂CH₂OH (J-13) (SEQ ID NO: 203)HO-A^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-G^(e1p)-A^(ms)-G^(ms)-U^(ms)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-G^(ms)-A^(ms)-A^(ms)-A^(ms)-C^(ms)-U^(ms)-G^(e1p)-A^(e1p)-G^(e1p)-C^(e1p)-A^(e1p)-CH₂CH₂OH (J-14) (SEQ ID NO: 204)HO-A^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-G^(e1p)-A^(e1p)-G^(e1p)-T^(e1p)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-G^(ms)-A^(ms)-A^(ms)-A^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-A^(e1p)-G^(e1p)-C^(e1p)-A^(e1p)-CH₂CH₂OH (J-15) (SEQ ID NO: 205)HO-A^(e1p)-A^(e1p)-A^(e1p)-C^(e1p)-T^(e1p)-G^(ms)-A^(ms)-G^(ms)-C^(ms)-A^(ms)-A^(ms)-A^(ms)-U^(ms)-T^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-T^(e1p)-CH₂CH₂OH (J-16) (SEQ ID NO: 203)HO-A^(e1s)-G^(e1s)-T^(e1s)-T^(e1s)-G^(e1s)-A^(ms)-G^(ms)-U^(ms)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-G^(ms)-A^(ms)-A^(ms)-A^(ms)-C^(ms)-U^(ms)-G^(e1s)-A^(e1s)-G^(e1s)-C^(e1s)-A^(e1s)-CH₂CH₂OH (J-17) (SEQ ID NO: 204)HO-A^(e1s)-G^(e1s)-T^(e1s)-T^(e1s)-G^(e1s)-A^(e1s)-G^(e1s)-T^(e1s)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-G^(ms)-A^(ms)-A^(ms)-A^(e1s)-C^(e1s)-T^(e1s)-G^(e1s)-A^(e1s)-G^(e1s)-C^(e1s)-A^(e1s)-CH₂CH₂OH (J-18) (SEQ ID NO: 205)HO-A^(e1s)-A^(e1s)-A^(e1s)-C^(e1s)-T^(e1s)-G^(ms)-A^(ms)-G^(ms)-C^(ms)-A^(ms)-A^(ms)-A^(ms)-U^(ms)-T^(e1s)-T^(e1s)-G^(e1s)-C^(e1s)-T^(e1s)-CH₂CH₂OHEspecially preferable are (J-1) to (J-9).

Preferable examples of the compound represented by general formula (II′)include the following compounds.

(k-1) (SEQ ID NO: 206)HO-T^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-C^(mp)-A^(mp)-A^(mp)-A^(mp)-A^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-CH₂CH₂OH (k-2) (SEQ ID NO: 206)HO-T^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-U^(ms)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-A^(ms)-A^(ms)-A^(ms)-A^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(e2s)-CH₂CH₂OH (k-3) (SEQ ID NO: 206)HO-T^(e2s)-T^(e2s)-G^(e2s)-A^(e2s)-G^(e2s)-U^(ms)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-A^(ms)-A^(ms)-A^(ms)-A^(e2s)-C^(e2s)-T^(e2s)-G^(e2s)-A^(e2s)-CH₂CH₂OH (k-4) (SEQ ID NO: 12)HO-T^(e2p)-T^(e2p)-G^(mp)-A^(mp)-G^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-A^(mp)-A^(mp)-A^(mp)-A^(mp)-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-CH₂CH₂OH (k-5) (SEQ ID NO: 12)HO-T^(e2p)-T^(e2p)-G^(ms)-A^(ms)-G^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-A^(ms)-A^(ms)-A^(ms)-A^(ms)-C^(e2p)-T^(e2p)-G^(ms)-A^(ms)-CH₂CH₂OH (k-6) (SEQ ID NO: 12)HO-T^(e2s)-T^(e2s)-G^(ms)-A^(ms)-G^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-T^(e2s)-C^(e2s)-A^(ms)-A^(ms)-A^(ms)-A^(ms)-C^(e2s)-T^(e2s)-G^(ms)-A^(ms)-CH₂CH₂OH (k-7) (SEQ ID NO: 207)HO-G^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-A^(mp)-A^(mp)-G^(mp)-U^(mp)-U^(mp)-G^(mp)-A^(mp)-G^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-CH₂CH₂OH (k-8) (SEQ ID NO: 207)HO-G^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-A^(ms)-A^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(ms)-A^(ms)-G^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-CH₂CH₂OH (k-9) (SEQ ID NO: 207)HO-G^(e2s)-T^(e2s)-G^(e2s)-C^(e2s)-A^(e2s)-A^(ms)-A^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(ms)-A^(ms)-G^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-T^(e2s)-C^(e2s)-CH₂CH₂OH (k-10) (SEQ ID NO: 13)HO-G^(mp)-T^(e2p)-G^(mp)-C^(e2p)-A^(mp)-A^(mp)-A^(mp)-G^(mp)-T^(e2p)-T^(e2p)-G^(mp)-A^(mp)-G^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-CH₂CH₂OH (k-11) (SEQ ID NO: 13)HO-G^(ms)-T^(e2p)-G^(ms)-C^(e2p)-A^(ms)-A^(ms)-A^(ms)-G^(mp)-T^(e2p)-T^(e2p)-G^(ms)-A^(ms)-G^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-CH₂CH₂OH (k-12) (SEQ ID NO: 13)HO-G^(ms)-T^(e2s)-G^(ms)-C^(e2s)-A^(ms)-A^(ms)-A^(ms)-G^(ms)-T^(e2s)-T^(e2s)-G^(ms)-A^(ms)-G^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-T^(e2s)-C^(e2s)-CH₂CH₂OH (k-13) (SEQ ID NO: 206)HO-T^(e1p)-T^(e1p)-G^(e1p)-A^(e1p)-G^(e1p)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-C^(mp)-A^(mp)-A^(mp)-A^(mp)-A^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-A^(e1p)-CH₂CH₂OH (k-14) (SEQ ID NO: 206)HO-T^(e1p)-T^(e1p)-G^(e1p)-A^(e1p)-G^(e1p)-U^(ms)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-A^(ms)-A^(ms)-A^(ms)-A^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-A^(e1s)-CH₂CH₂OH (k-15) (SEQ ID NO: 206)HO-T^(e1s)-T^(e1s)-G^(e1s)-A^(e1s)-G^(e1s)-U^(ms)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-A^(ms)-A^(ms)-A^(ms)-A^(e1s)-C^(e1s)-T^(e1s)-G^(e1s)-A^(e1s)-CH₂CH₂OH (k-16) (SEQ ID NO: 12)HO-T^(e1p)-T^(e1p)-G^(mp)-A^(mp)-G^(mp)-T^(e1p)-C^(e1p)-T^(e1p)-T^(e1p)-C^(e1p)-A^(mp)-A^(mp)-A^(mp)-A^(mp)-C^(e1p)-T^(e1p)-G^(mp)-A^(mp)-CH₂CH₂OH (k-17) (SEQ ID NO: 12)HO-T^(e1p)-T^(e1p)-G^(ms)-A^(ms)-G^(ms)-T^(e1p)-C^(e1p)-T^(e1p)-T^(e1p)-C^(e1p)-A^(ms)-A^(ms)-A^(ms)-A^(ms)-C^(e1p)-T^(e1p)-G^(ms)-A^(ms)-CH₂CH₂OH (k-18) (SEQ ID NO: 12)HO-T^(e1s)-T^(e1s)-G^(ms)-A^(ms)-G^(ms)-T^(e1s)-C^(e1s)-T^(e1s)-T^(e1s)-C^(e1s)-A^(ms)-A^(ms)-A^(ms)-A^(ms)-C^(e1s)-T^(e1s)-G^(ms)-A^(ms)-CH₂CH₂OH (k-19) (SEQ ID NO: 207)HO-G^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-A^(e1p)-A^(mp)-A^(mp)-G^(mp)-U^(mp)-U^(mp)-G^(mp)-A^(mp)-G^(mp)-T^(e1p)-C^(e1p)-T^(e1p)-T^(e1p)-C^(e1p)-CH₂CH₂OH (k-20) (SEQ ID NO: 207)HO-G^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-A^(e1p)-A^(ms)-A^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(ms)-A^(ms)-G^(ms)-T^(e1p)-C^(e1p)-T^(e1p)-T^(e1p)-C^(e1p)-CH₂CH₂OH (k-21) (SEQ ID NO: 207)HO-G^(e1s)-T^(e1s)-G^(e1s)-C^(e1s)-A^(e1s)-A^(ms)-A^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(ms)-A^(ms)-G^(ms)-T^(e1s)-C^(e1s)-T^(e1s)-T^(e1s)-C^(e1s)-CH₂CH₂OH (k-22) (SEQ ID NO: 13)HO-G^(mp)-T^(e1p)-G^(mp)-C^(e1p)-A^(mp)-A^(mp)-A^(mp)-G^(mp)-T^(e1p)-T^(e1p)-G^(mp)-A^(mp)-G^(mp)-T^(e1p)-C^(e1p)-T^(e1p)-T^(e1p)-C^(e1p)-CH₂CH₂OH (k-23) (SEQ ID NO: 13)HO-G^(ms)-T^(e1p)-G^(ms)-C^(e1p)-A^(ms)-A^(ms)-A^(ms)-G^(m)-T^(e1p)-T^(e1p)-G^(ms)-A^(ms)-G^(ms)-T^(e1p)-C^(e1p)-T^(e1p)-T^(e1p)-C^(e1p)-CH₂CH₂OH

(k-24) (SEQ ID NO: 13)HO-G^(ms)-T^(e1s)-G^(ms)-C^(e1s)-A^(ms)-A^(ms)-A^(ms)-G^(m)-T^(e1s)-T^(e1s)-G^(ms)-A^(ms)-G^(ms)-T^(e1s)-C^(e1s)-T^(e1s)-T^(e1s)-C^(e1s)-CH₂CH₂OHEspecially preferable are (k-1) to (k-12).

Preferable examples of the compound represented by general formula(III′) include the following compounds.

(m-1) (SEQ ID NO: 208)HO-G^(e2p)-C^(e2p)-C^(e2p)-G^(e2p)-C^(e2p)-U^(mp)-G^(mp)-C^(mp)-C^(mp)-C^(mp)-A^(e2p)-A^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-CH₂CH₂OH (m-2) (SEQ IDNO: 208)HO-G^(e2p)-C^(e2p)-C^(e2p)-G^(e2p)-C^(e2p)-U^(ms)-G^(ms)-C^(ms)-C^(ms)-C^(ms)-A^(e2p)-A^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-CH₂CH₂OH (m-3) (SEQ IDNO: 208)HO-G^(e2s)-C^(e2s)-C^(e2s)-G^(e2s)-C^(e2s)-U^(ms)-G^(ms)-C^(ms)-C^(ms)-C^(ms)-A^(e2s)-A^(e2s)-T^(e2s)-G^(e2s)-C^(e2s)-CH₂CH₂OH (m-4) (SEQ IDNO: 209)HO-C^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-C^(e2p)-C^(e2p)-A^(mp)-A^(mp)-T^(e2p)-G^(mp)-C^(e2p)-C^(e2p)-A^(mp)-U^(mp)-C^(e2p)-C^(e2p)-CH₂CH₂OH(m-5) (SEQ ID NO: 209)HO-C^(e2p)-G^(ms)-C^(e2p)-T^(e2p)-G^(ms)-C^(ms)-C^(e2p)-C^(e2p)-A^(ms)-A^(ms)-T^(e2p)-G^(ms)-C^(e2p)-C^(e2p)-A^(ms)-U^(ms)-C^(e2p)-C^(e2p)-CH₂CH₂OH(m-6) (SEQ ID NO: 209)HO-C^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-G^(ms)-C^(ms)-C^(e2s)-C^(e2s)-A^(ms)-A^(ms)-T^(e2s)-G^(ms)-C^(e2s)-C^(e2s)-A^(ms)-U^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OH(m-7) (SEQ ID NO: 208)HO-G^(e1p)-C^(e1p)-C^(e1p)-G^(e1p)-C^(e1p)-U^(mp)-G^(mp)-C^(mp)-C^(mp)-C^(mp)-A^(e1p)-A^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-CH₂CH₂OH (m-8) (SEQ IDNO: 208)HO-G^(e1p)-C^(e1p)-C^(e1p)-G^(e1p)-C^(e1p)-U^(ms)-G^(ms)-C^(ms)-C^(ms)-C^(ms)-A^(e1p)-A^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-CH₂CH₂OH (m-9) (SEQ IDNO: 208)HO-G^(e1s)-C^(e1s)-C^(e1s)-G^(e1s)-C^(e1s)-U^(ms)-G^(ms)-C^(ms)-C^(ms)-C^(ms)-A^(e1s)-A^(e1s)-T^(e1s)-G^(e1s)-C^(e1s)-CH₂CH₂OH (m-10) (SEQ IDNO: 209)HO-C^(e1p)-G^(mp)-C^(e1p)-T^(e1p)-G^(mp)-C^(e1p)-C^(e1p)-C^(e1p)-A^(mp)-A^(mp)-T^(e1p)-G^(mp)-C^(e1p)-C^(e1p)-A^(mp)-U^(mp)-C^(e1p)-C^(e1p)-CH₂CH₂OH (m-11) (SEQ ID NO: 209)HO-C^(e1p)-G^(ms)-C^(e1p)-T^(e1p)-G^(ms)-C^(e1p)-C^(e1p)-C^(e1p)-A^(ms)-A^(ms)-T^(e1p)-G^(ms)-C^(e1p)-C^(e1p)-A^(ms)-U^(ms)-C^(e1p)-C^(e1p)-CH₂CH₂OH (m-12) (SEQ ID NO: 209)HO-C^(e1s)-G^(ms)-C^(e1s)-T^(e1s)-G^(ms)-C^(e1s)-C^(e1s)-C^(e1s)-A^(ms)-A^(ms)-T^(e1s)-G^(ms)-C^(e1s)-C^(e1s)-A^(ms)-U^(ms)-C^(e1s)-C^(e1s)-CH₂CH₂OHEspecially preferable are (m-1) to (m-6).

Preferable examples of the compound represented by general formula (IV′)include the following compounds.

(n-1) (SEQ ID NO: 210)HO-C^(e2p)-A^(mp)-G^(mp)-T^(e2p)-T^(e2p)-U^(mp)-G^(mp)-C^(e2p)-C^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-C^(e2p)-C^(e2p)-C^(e2p)-A^(mp)-A^(mp)-CH₂CH₂OH(n-2) (SEQ ID NO: 17)HO-T^(e2p)-G^(mp)-T^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-C^(e2p)-A^(mp)-A^(mp)-C^(e2p)-A^(mp)-G^(mp)-T^(e2p)-T^(e2p)-T^(e2p)-G^(mp)-CH₂CH₂OH (n-3) (SEQ ID NO: 210)HO-C^(e2p)-A^(ms)-G^(ms)-T^(e2p)-T^(e2p)-U^(ms)-G^(ms)-C^(e2p)-C^(e2p)-G^(ms)-C^(e2p)-T^(e2p)-G^(ms)-C^(e2p)-C^(e2p)-C^(e2p)-A^(ms)-A^(ms)-CH₂CH₂OH(n-4) (SEQ ID NO: 17)HO-T^(e2p)-G^(ms)-T^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(ms)-A^(ms)-C^(e2p)-A^(ms)-A^(ms)-C^(e2p)-A^(ms)-G^(ms)-T^(e2p)-T^(e2p)-T^(e2p)-G^(ms)-CH₂CH₂OH (n-5) (SEQ ID NO: 210)HO-C^(e2s)-A^(ms)-G^(ms)-T^(e2s)-T^(e2s)-U^(ms)-G^(ms)-C^(e2s)-C^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-G^(ms)-C^(e2s)-C^(e2s)-C^(e2s)-A^(ms)-A^(ms)-CH₂CH₂OH(n-6) (SEQ ID NO: 17)HO-T^(e2s)-G^(ms)-T^(e2s)-T^(e2s)-C^(e2s)-T^(e2s)-G^(ms)-A^(ms)-C^(e2s)-A^(ms)-A^(ms)-C^(e2s)-A^(ms)-G^(ms)-T^(e2s)-T^(e2s)-T^(e2s)-G^(ms)-CH₂CH₂OH (n-7) (SEQ ID NO: 210)HO-C^(e1p)-A^(mp)-G^(mp)-T^(e1p)-T^(e1p)-U^(mp)-G^(mp)-C^(e1p)-C^(e1p)-G^(mp)-C^(e1p)-T^(e1p)-G^(mp)-C^(e1p)-C^(e1p)-C^(e1p)-A^(mp)-A^(mp)-CH₂CH₂OH(n-8) (SEQ ID NO: 17)HO-T^(e1p)-G^(mp)-T^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-G^(mp)-A^(mp)-C^(e1p)-A^(mp)-A^(mp)-C^(e1p)-A^(mp)-G^(mp)-T^(e1p)-T^(e1p)-T^(e1p)-G^(mp)-CH₂CH₂OH (n-9) (SEQ ID NO: 210)HO-C^(e1p)-A^(ms)-G^(ms)-T^(e1p)-T^(e1p)-U^(ms)-G^(ms)-C^(e1p)-C^(e1p)-G^(ms)-C^(e1p)-T^(e1p)-G^(ms)-C^(e1p)-C^(e1p)-C^(e1p)-A^(ms)-A^(ms)-CH₂CH₂OH(n-10) (SEQ ID NO: 17)HO-T^(e1p)-G^(ms)-T^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-G^(ms)-A^(ms)-C^(e1p)-A^(ms)-A^(ms)-C^(e1p)-A^(ms)-G^(ms)-T^(e1p)-T^(e1p)-T^(e1p)-G^(ms)-CH₂CH₂OH (n-11) (SEQ ID NO: 210)HO-C^(e1s)-A^(ms)-G^(ms)-T^(e1s)-T^(e1s)-U^(ms)-G^(ms)-C^(e1s)-C^(e1s)-G^(ms)-C^(e1s)-T^(e1s)-G^(ms)-C^(e1s)-C^(e1s)-C^(e1s)-A^(ms)-A^(ms)-CH₂CH₂OH (n-12) (SEQ ID NO: 17)HO-T^(e1s)-G^(ms)-T^(e1s)-T^(e1s)-C^(e1s)-T^(e1s)-G^(ms)-A^(ms)-C^(e1s)-A^(ms)-A^(ms)-C^(e1s)-A^(ms)-G^(ms)-T^(e1s)-T^(e1s)-T^(e1s)-G^(ms)-CH₂CH₂OHEspecially preferable are (m-1), (m-3) and (m-5).

Preferable examples of the compound represented by general formula (V′)include the following compounds.

(o-1) (SEQ ID NO: 211)HO-G^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-T^(e2p)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-U^(mp)-U^(mp)-A^(mp)-G^(mp)-U^(mp)-U^(mp)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-CH₂CH₂OH (o-2) (SEQ ID NO: 211)HO-G^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-T^(e2p)-U^(ms)-C^(ms)-U^(ms)-U^(ms)-U^(ms)-U^(ms)-A^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-CH₂CH₂OH (o-3) (SEQ ID NO: 211)HO-G^(e2s)-C^(e2s)-T^(e2s)-T^(e2s)-T^(e2s)-U^(ms)-C^(ms)-U^(ms)-U^(ms)-U^(ms)-U^(ms)-A^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(e2s)-C^(e2s)-T^(e2s)-G^(e2s)-C^(e2s)-CH₂CH₂OH (o-4) (SEQ ID NO: 212)HO-C^(mp)-U^(mp)-U^(mp)-U^(mp)-U^(mp)-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-U^(mp)-U^(mp)-U^(mp)-C^(mp)-C^(mp)-CH₂CH₂OH (o-5) (SEQ ID NO: 212)HO-C^(ms)-U^(ms)-U^(ms)-U^(ms)-U^(ms)-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-U^(ms)-U^(ms)-U^(ms)-C^(ms)-C^(ms)-CH₂CH₂OH (o-6) (SEQ ID NO: 212)HO-C^(ms)-U^(ms)-U^(ms)-U^(ms)-U^(ms)-A^(e2s)-G^(e2s)-T^(e2s)-T^(e2s)-G^(e2s)-C^(e2s)-T^(e2s)-G^(e2s)-C^(e2s)-T^(e2s)-C^(e2s)-T^(e2s)-U^(ms)-U^(ms)-U^(ms)-C^(ms)-C^(ms)-CH₂CH₂OH (o-7) (SEQ ID NO: 211)HO-G^(e1p)-C^(e1p)-T^(e1p)-T^(e1p)-T^(e1p)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-U^(mp)-U^(mp)-A^(mp)-G^(mp)-U^(mp)-U^(mp)-G^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-CH₂CH₂OH (o-8) (SEQ ID NO: 211)HO-G^(e1p)-C^(e1p)-T^(e1p)-T^(e1p)-T^(e1p)-U^(ms)-C^(ms)-U^(ms)-U^(ms)-U^(ms)-U^(ms)-A^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-CH₂CH₂OH (o-9) (SEQ ID NO: 211)HO-G^(e1s)-C^(e1s)-T^(e1s)-T^(e1s)-T^(e1s)-U^(ms)-C^(ms)-U^(ms)-U^(ms)-U^(ms)-U^(ms)-A^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(e1s)-C^(e1s)-T^(e1s)-G^(e1s)-C^(e1s)-CH₂CH₂OH (o-10) (SEQ ID NO: 212)HO-C^(mp)-U^(mp)-U^(mp)-U^(mp)-U^(mp)-A^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-U^(mp)-U^(mp)-U^(mp)-C^(mp)-C^(mp)-CH₂CH₂OH (o-11) (SEQ ID NO: 212)HO-C^(ms)-U^(ms)-U^(ms)-U^(ms)-U^(ms)-A^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-T^(e1p)-G^(e1p)-C^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-U^(ms)-U^(ms)-U^(ms)-C^(ms)-C^(ms)-CH₂CH₂OH (o-12) (SEQ ID NO: 212)HO-C^(ms)-U^(ms)-U^(ms)-U^(ms)-U^(ms)-A^(e1s)-G^(e1s)-T^(e1s)-T^(e1s)-G^(e1s)-C^(e1s)-T^(e1s)-G^(e1s)-C^(e1s)-T^(e1s)-C^(e1s)-T^(e1s)-U^(ms)-U^(ms)-U^(ms)-C^(ms)-C^(ms)-CH₂CH₂OHEspecially preferable are (o-1) to (o-6).

Preferable examples of the compound represented by general formula (VI′)include the following compounds.

(p-1) (SEQ ID NO: 213)HO-T^(e2p)-T^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-C^(mp)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-U^(mp)-C^(mp)-A^(mp)-A^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-G^(e2p)-CH₂CH₂OH(p-2) (SEQ ID NO: 213)HO-T^(e2p)-T^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-C^(ms)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-U^(ms)-C^(ms)-A^(ms)-A^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-G^(e2p)-CH₂CH₂OH(p-3) (SEQ ID NO: 213)HO-T^(e2s)-T^(e2s)-T^(e2s)-T^(e2s)-C^(e2s)-C^(ms)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-U^(ms)-C^(ms)-A^(ms)-A^(e2s)-G^(e2s)-T^(e2s)-G^(e2s)-G^(e2s)-CH₂CH₂OH(p-4) (SEQ ID NO: 213)HO-T^(e1p)-T^(e1p)-T^(e1p)-T^(e1p)-C^(e1p)-C^(mp)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-U^(mp)-C^(mp)-A^(mp)-A^(e1p)-G^(e1p)-T^(e1p)-G^(e1p)-G^(e1p)-CH₂CH₂OH(p-5) (SEQ ID NO: 213)HO-T^(e1p)-T^(e1p)-T^(e1p)-T^(e1p)-C^(e1p)-C^(ms)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-U^(ms)-C^(ms)-A^(ms)-A^(e1p)-G^(e1p)-T^(e1p)-G^(e1p)-G^(e1p)-CH₂CH₂OH(p-6) (SEQ ID NO: 213)HO-T^(e1s)-T^(e1s)-T^(e1s)-T^(e1s)-C^(e1s)-C^(ms)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-U^(ms)-C^(ms)-A^(ms)-A^(e1s)-G^(e1s)-T^(e1s)-G^(e1s)-G^(e1s)-CH₂CH₂OHEspecially preferable are (p-1) to (p-3).

Preferable examples of the compound represented by general formula(VII′) include the following compounds.

(q-1) (SEQ ID NO: 214)HO-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-U^(mp)-C^(mp)-C^(mp)-U^(mp)-C^(mp)-C^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH (q-2) (SEQ ID NO: 215)HO-G^(e2p)-T^(e2p)-T^(e2p)-A^(e2p)-T^(e2p)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-U^(mp)-C^(mp)-C^(mp)-U^(mp)-C^(mp)-C^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH (q-3) (SEQ ID NO: 23)HO-C^(e2p)-U^(mp)-G^(mp)-C^(e2p)-U^(mp)-U^(mp)-C^(e2p)-C^(e2p)-U^(mp)-C^(e2p)-C^(e2p)-A^(mp)-A^(mp)-C^(e2p)-C^(e2p)-CH₂CH₂OH (q-4) (SEQ ID NO: 214)HO-C^(e2p)-T^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-U^(mp)-C^(mp)-C^(e2p)-U^(mp)-C^(mp)-C^(e2p)-A^(mp)-A^(mp)-C^(e2p)-C^(e2p)-CH₂CH₂OH (q-5) (SEQ ID NO: 214)HO-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-U^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(ms)-C^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH (q-6) (SEQ ID NO: 215)HO-G^(e2p)-T^(e2p)-T^(e2p)-A^(e2p)-T^(e2p)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(ms)-C^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH (q-7) (SEQ ID NO: 23)HO-C^(e2s)-U^(ms)-G^(ms)-C^(e2s)-U^(ms)-U^(ms)-C^(e2s)-C^(e2s)-U^(ms)-C^(e2s)-C^(e2s)-A^(ms)-A^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OH (q-8) (SEQ ID NO: 214)HO-C^(e2s)-T^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-U^(ms)-C^(ms)-C^(e2s)-U^(ms)-C^(ms)-C^(e2s)-A^(ms)-A^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OH (q-9) (SEQ ID NO: 214)HO-C^(e2s)-T^(e2s)-G^(e2s)-C^(e2s)-T^(e2s)-U^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(ms)-C^(e2s)-A^(e2s)-A^(e2s)-C^(e2s)-C^(e2s)-CH₂CH₂OH (q-10) (SEQ ID NO: 215)HO-G^(e2s)-T^(e2s)-T^(e2s)-A^(e2s)-T^(e2s)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(ms)-C^(e2s)-A^(e2s)-A^(e2s)-C^(e2s)-C^(e2s)-CH₂CH₂OH (q-11) (SEQ ID NO: 23)HO-C^(e2s)-U^(ms)-G^(ms)-C^(e2s)-U^(ms)-U^(ms)-C^(e2s)-C^(e2s)-U^(ms)-C^(e2s)-C^(e2s)-A^(ms)-A^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OH (q-12) (SEQ ID NO: 214)HO-C^(e2s)-T^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-U^(ms)-C^(ms)-C^(e2s)-U^(ms)-C^(ms)-C^(e2s)-A^(ms)-A^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OH (q-13) (SEQ ID NO: 214)HO-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-U^(mp)-C^(mp)-C^(mp)-U^(mp)-C^(mp)-C^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH (q-14) (SEQ ID NO: 215)HO-G^(e2p)-T^(e2p)-T^(e2p)-A^(e2p)-T^(e2p)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-U^(mp)-C^(mp)-C^(mp)-U^(mp)-C^(mp)-C^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH (q-15) (SEQ ID NO: 23)HO-C^(e2p)-U^(mp)-G^(mp)-C^(e2p)-U^(mp)-U^(mp)-C^(e2p)-C^(e2p)-U^(mp)-C^(e2p)-C^(e2p)-A^(mp)-A^(mp)-C^(e2p)-C^(e2p)-CH₂CH₂OH (q-16) (SEQ ID NO: 214)HO-C^(e2p)-T^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-U^(mp)-C^(mp)-C^(e2p)-U^(mp)-C^(mp)-C^(e2p)-A^(mp)-A^(mp)-C^(e2p)-C^(e2p)-CH₂CH₂OH (q-17) (SEQ ID NO:214)HO-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-U^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(ms)-C^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH (q-18) (SEQ ID NO: 215)HO-G^(e2p)-T^(e2p)-T^(e2p)-A^(e2p)-T^(e2p)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(ms)-C^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH (q-19) (SEQ ID NO: 23)HO-C^(e2s)-U^(ms)-G^(ms)-C^(e2s)-U^(ms)-U^(ms)-C^(e2s)-C^(e2s)-U^(ms)-C^(e2s)-C^(e2s)-A^(ms)-A^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OH (q-20) (SEQ ID NO: 214)HO-C^(e2s)-T^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-U^(ms)-C^(ms)-C^(e2s)-U^(ms)-C^(ms)-C^(e2s)-A^(ms)-A^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OH (q-21) (SEQ ID NO: 214)HO-C^(e2s)-T^(e2s)-G^(e2s)-C^(e2s)-T^(e2s)-U^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(ms)-C^(e2s)-A^(e2s)-A^(e2s)-C^(e2s)-C^(e2s)-CH₂CH₂OH (q-22) (SEQ ID NO: 215)HO-G^(e2s)-T^(e2s)-T^(e2s)-A^(e2s)-T^(e2s)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-U^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(ms)-C^(e2s)-A^(e2s)-A^(e2s)-C^(e2s)-C^(e2s)-CH₂CH₂OH (q-23) (SEQ ID NO: 23)HO-C^(e2s)-U^(ms)-G^(ms)-C^(e2s)-U^(ms)-U^(ms)-C^(e2s)-C^(e2s)-U^(ms)-C^(e2s)-C^(e2s)-A^(ms)-A^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OH (q-24) (SEQ ID NO: 214)HO-C^(e2s)-T^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-U^(ms)-C^(ms)-C^(e2s)-U^(ms)-C^(ms)-C^(e2s)-A^(ms)-A^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OHEspecially preferable are (q-1) to (q-12).

Preferable examples of the compound represented by general formula (I′)include the following compounds.

(I″-1) (SEQ ID NO:)HO-G^(mp)-T^(e2p)-A^(mp)-U^(mp)-T^(e2p)-T^(e2p)-A^(mp)-G^(mp)-C^(e2p)-A^(mp)-T^(e2p)-G^(mp)-U^(mp)-T^(e2p)-C^(mp)-C^(e2p)-C^(e2p)-A^(mp)-CH₂CH₂OH(I″-2) (SEQ ID NO:)HO-C^(e2p)-C^(e2p)-A^(mp)-U^(mp)-T^(e2p)-U^(mp)-G^(mp)-T^(e2p)-A^(mp)-U^(mp)-T^(e2p)-T^(e2p)-A^(mp)-G^(mp)-C^(e2p)-A^(mp)-T^(e2p)-G^(mp)-CH₂CH₂OH(I″-3) (SEQ ID NO: 34)HO-G^(mp)-T^(e1p)-A^(mp)-U^(mp)-T^(e1p)-T^(e1p)-A^(mp)-G^(mp)-C^(e1p)-A^(mp)-T^(e1p)-G^(mp)-U^(mp)-T^(e1p)-C^(mp)-C^(e1p)-C^(e1p)-A^(mp)-CH₂CH₂OH(I″-4) (SEQ ID NO: 39)HO-C^(e1p)-C^(e1p)-A^(mp)-U^(mp)-T^(e1p)-U^(mp)-G^(mp)-T^(e1p)-A^(mp)-U^(mp)-T^(e1p)-T^(e1p)-A^(mp)-G^(mp)-C^(e1p)-A^(mp)-T^(e1p)-G^(mp)-CH₂CH₂OH(I″-5) (SEQ ID NO: 34)HO-G^(ms)-T^(e2p)-A^(ms)-U^(ms)-T^(e2p)-T^(e2p)-A^(ms)-G^(ms)-C^(e2p)-A^(ms)-T^(e2p)-G^(ms)-U^(ms)-T^(e2p)-C^(ms)-C^(e2p)-C^(e2p)-A^(ms)-CH₂CH₂OH(I″-6) (SEQ ID NO: 39)HO-C^(e2p)-C^(e2p)-A^(ms)-U^(ms)-T^(e2p)-U^(ms)-G^(ms)-T^(e2p)-A^(ms)-U^(ms)-T^(e2p)-T^(e2p)-A^(ms)-G^(ms)-C^(e2p)-A^(ms)-T^(e2p)-G^(ms)-CH₂CH₂OH(I″-7) (SEQ ID NO: 34)HO-G^(ms)-T^(e1p)-A^(ms)-U^(ms)-T^(e1p)-T^(e1p)-A^(ms)-G^(ms)-C^(e1p)-A^(ms)-T^(e1p)-G^(ms)-U^(ms)-T^(e1p)-C^(ms)-C^(e1p)-C^(e1p)-A^(ms)-CH₂CH₂OH(I″-8) (SEQ ID NO: 39)HO-C^(e1p)-C^(e1p)-A^(ms)-U^(ms)-T^(e1p)-U^(ms)-G^(ms)-T^(e1p)-A^(ms)-U^(ms)-T^(e1p)-T^(e1p)-A^(ms)-G^(ms)-C^(e1p)-A^(ms)-T^(e1p)-G^(ms)-CH₂CH₂OH(I″-9) (SEQ ID NO: 34)HO-G^(ms)-T^(e2s)-A^(ms)-U^(ms)-T^(e2s)-T^(e2s)-A^(ms)-G^(ms)-C^(e2s)-A^(ms)-T^(e2s)-G^(ms)-U^(ms)-T^(e2s)-C^(ms)-C^(e2s)-C^(e2s)-A^(ms)-CH₂CH₂OH(I″-10) (SEQ ID NO: 39)HO-C^(e2s)-C^(e2s)-A^(ms)-U^(ms)-T^(e2s)-U^(ms)-G^(ms)-T^(e2s)-A^(ms)-U^(ms)-T^(e2s)-T^(e2s)-A^(ms)-G^(ms)-C^(e2s)-A^(ms)-T^(e2s)-G^(ms)-CH₂CH₂OH(I″-11) (SEQ ID NO: 34)HO-G^(ms)-T^(e1s)-A^(ms)-U^(ms)-T^(e1s)-T^(e1s)-A^(ms)-G^(ms)-C^(e1s)-A^(ms)-T^(e1s)-G^(ms)-U^(ms)-T^(e1s)-C^(ms)-C^(e1s)-C^(e1s)-A^(ms)-CH₂CH₂OH(I″-12) (SEQ ID NO: 39)HO-C^(e1s)-C^(e1s)-A^(ms)-U^(ms)-T^(e1s)-U^(ms)-G^(ms)-T^(e1s)-A^(ms)-U^(ms)-T^(e1s)-T^(e1s)-A^(ms)-G^(ms)-C^(e1s)-A^(ms)-T^(e1s)-G^(ms)-CH₂CH₂OHEspecially preferable are (I″-1), (I″-2), (I″-9) and (I″-10).

Preferable examples of the compound represented by general formula (II″)include the following compounds.

(II″-1) (SEQ ID NO: 35)HO-A^(mp)-G^(mp)-C^(e2p)-A^(mp)-T^(e2p)-G^(mp)-T^(e2p)-T^(e2p)-C^(mp)-C^(mp)-C^(e2p)-A^(mp)-A^(mp)-T^(e2p)-U^(mp)-C^(mp)-T^(e2p)-C^(e2p)-CH₂CH₂OH(II″-2) (SEQ ID NO: 38)HO-T^(e2p)-U^(mp)-C^(e2p)-C^(mp)-C^(e2p)-A^(mp)-A^(mp)-T^(e2p)-U^(mp)-C^(mp)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-G^(mp)-A^(e2p)-A^(mp)-T^(e2p)-CH₂CH₂OH(II″-3) (SEQ ID NO: 35)HO-A^(mp)-G^(mp)-C^(e1p)-A^(mp)-T^(e1p)-G^(mp)-T^(e1p)-T^(e1p)-C^(mp)-C^(mp)-C^(e1p)-A^(mp)-A^(mp)-T^(e1p)-U^(mp)-C^(mp)-T^(e1p)-C^(e1p)-CH₂CH₂OH(II″-4) (SEQ ID NO: 38)HO-T^(e1p)-U^(mp)-C^(e1p)-C^(mp)-C^(e1p)-A^(mp)-A^(mp)-T^(e1p)-U^(mp)-C^(mp)-T^(e1p)-C^(e1p)-A^(mp)-G^(mp)-G^(mp)-A^(e1p)-A^(mp)-T^(e1p)-CH₂CH₂OH(II″-5) (SEQ ID NO: 35)HO-A^(ms)-G^(ms)-C^(e2p)-A^(ms)-T^(e2p)-G^(ms)-T^(e2p)-T^(e2p)-C^(ms)-C^(ms)-C^(e2p)-A^(ms)-A^(ms)-T^(e2p)-U^(ms)-C^(ms)-T^(e2p)-C^(e2p)-CH₂CH₂OH(II″-6) (SEQ ID NO: 38)HO-T^(e2p)-U^(ms)-C^(e2p)-C^(ms)-C^(e2p)-A^(ms)-A^(ms)-T^(e2p)-U^(ms)-C^(ms)-T^(e2p)-C^(e2p)-A^(ms)-G^(ms)-G^(ms)-A^(e2p)-A^(ms)-T^(e2p)-CH₂CH₂OH(II″-7) (SEQ ID NO: 35)HO-A^(ms)-G^(ms)-C^(e1p)-A^(ms)-T^(e1p)-G^(ms)-T^(e1p)-T^(e1p)-C^(ms)-C^(ms)-C^(e1p)-A^(ms)-A^(ms)-T^(e1p)-U^(ms)-C^(ms)-T^(e1p)-C^(e1p)-CH₂CH₂OH(II″-8) (SEQ ID NO: 38)HO-T^(e1p)-U^(ms)-C^(e1p)-C^(ms)-C^(e1p)-A^(ms)-A^(ms)-T^(e1p)-U^(ms)-C^(ms)-T^(e1p)-C^(e1p)-A^(ms)-G^(ms)-G^(ms)-A^(e1p)-A^(ms)-T^(e1p)-CH₂CH₂OH(II″-9) (SEQ ID NO: 35)HO-A^(ms)-G^(ms)-C^(e2s)-A^(ms)-T^(e2s)-G^(ms)-T^(e2s)-T^(e2s)-C^(ms)-C^(ms)-C^(e2s)-A^(ms)-A^(ms)-T^(e2s)-U^(ms)-C^(ms)-T^(e2s)-C^(e2s)-CH₂CH₂OH(II″-10) (SEQ ID NO: 38)HO-T^(e2s)-U^(ms)-C^(e2s)-C^(ms)-C^(e2s)-A^(ms)-A^(ms)-T^(e2s)-U^(ms)-C^(ms)-T^(e2s)-C^(e2s)-A^(ms)-G^(ms)-G^(ms)-A^(e2s)-A^(ms)-T^(e2s)-CH₂CH₂OH(II″-11) (SEQ ID NO: 35)HO-A^(ms)-G^(ms)-C^(e1s)-A^(ms)-T^(e1s)-G^(ms)-T^(e1s)-T^(e1s)-C^(ms)-C^(ms)-C^(e1s)-A^(ms)-A^(ms)-T^(e1s)-U^(ms)-C^(ms)-T^(e1s)-C^(e1s)-CH₂CH₂OH(II″-12) (SEQ ID NO: 38)HO-T^(e1s)-U^(ms)-C^(e1s)-C^(ms)-C^(e1s)-A^(ms)-A^(ms)-T^(e1s)-U^(ms)-C^(ms)-T^(e1s)-C^(e1s)-A^(ms)-G^(ms)-G^(ms)-A^(e1s)-A^(ms)-T^(e1s)-CH₂CH₂OHEspecially preferable are (II″-1), (II″-2), (II″-9) and (II″-10).

Preferable examples of the compound represented by general formula(III″) include the following compounds.

(III″-1) (SEQ ID NO: 30)HO-G^(mp)-A^(e2p)-A^(mp)-A^(mp)-A^(mp)-C^(e2p)-G^(mp)-C^(e2p)-C^(e2p)-G^(mp)-C^(mp)-C^(e2p)-A^(mp)-T^(e2p)-U^(mp)-U^(mp)-C^(e2p)-T^(e2p)-CH₂CH₂OH(III″-2) (SEQ ID NO: 36)HO-G^(mp)-C^(e2p)-C^(e2p)-G^(mp)-C^(e2p)-C^(mp)-A^(mp)-T^(e2p)-U^(mp)-U^(mp)-C^(e2p)-U^(mp)-C^(e2p)-A^(mp)-A^(mp)-C^(e2p)-A^(e2p)-G^(mp)-CH₂CH₂OH(III″-3) (SEQ ID NO: 37)HO-C^(e2p)-A^(mp)-T^(e2p)-A^(mp)-A^(mp)-T^(e2p)-G^(mp)-A^(mp)-A^(e2p)-A^(mp)-A^(mp)-C^(e2p)-G^(mp)-C^(mp)-C^(e2p)-G^(mp)-C^(e2p)-C^(e2p)-CH₂CH₂OH(III″-4) (SEQ ID NO: 30)HO-G^(mp)-A^(e1p)-A^(mp)-A^(mp)-A^(mp)-C^(e1p)-G^(mp)-C^(e1p)-C^(e1p)-G^(mp)-C^(mp)-C^(e1p)-A^(mp)-T^(e1p)-U^(mp)-U^(mp)-C^(e1p)-T^(e1p)-CH₂CH₂OH(III″-5) (SEQ ID NO: 36)HO-G^(mp)-C^(e1p)-C^(e1p)-G^(mp)-C^(e1p)-C^(mp)-A^(mp)-T^(e1p)-U^(mp)-U^(mp)-C^(e1p)-U^(mp)-C^(e1p)-A^(mp)-A^(mp)-C^(e1p)-A^(e1p)-G^(mp)-CH₂CH₂OH(III″-6) (SEQ ID NO: 37)HO-C^(e1p)-A^(mp)-T^(e1p)-A^(mp)-A^(mp)-T^(e1p)-G^(mp)-A^(mp)-A^(e1p)-A^(mp)-A^(mp)-C^(e1p)-G^(mp)-C^(mp)-C^(e1p)-G^(mp)-C^(e1p)-C^(e1p)-CH₂CH₂OH(III″-7) (SEQ ID NO: 30)HO-G^(ms)-A^(e2p)-A^(ms)-A^(ms)-A^(ms)-C^(e2p)-G^(ms)-C^(e2p)-C^(e2p)-G^(ms)-C^(ms)-C^(e2p)-A^(ms)-T^(e2p)-U^(ms)-U^(ms)-C^(e2p)-T^(e2p)-CH₂CH₂OH(III″-8) (SEQ ID NO: 36)HO-G^(ms)-C^(e2p)-C^(e2p)-G^(ms)-C^(e2p)-C^(ms)-A^(ms)-T^(e2p)-U^(ms)-U^(ms)-C^(e2p)-U^(ms)-C^(e2p)-A^(ms)-A^(ms)-C^(e2p)-A^(e2p)-G^(ms)-CH₂CH₂OH(III″-9) (SEQ ID NO: 37)HO-C^(e2p)-A^(ms)-T^(e2p)-A^(ms)-A^(ms)-T^(e2p)-G^(ms)-A^(ms)-A^(e2p)-A^(ms)-A^(ms)-C^(e2p)-G^(ms)-C^(ms)-C^(e2p)-G^(ms)-C^(e2p)-C^(e2p)-CH₂CH₂OH(III″-10) (SEQ ID NO: 30)HO-G^(ms)-A^(e1p)-A^(ms)-A^(ms)-A^(ms)-C^(e1p)-G^(ms)-C^(e1p)-C^(e1p)-G^(ms)-C^(ms)-C^(e1p)-A^(ms)-T^(e1p)-U^(ms)-U^(ms)-C^(e1p)-T^(e1p)-CH₂CH₂OH(III″-11) (SEQ ID NO: 36)HO-G^(ms)-C^(e1p)-C^(e1p)-G^(ms)-C^(e1p)-C^(ms)-A^(ms)-T^(e1p)-U^(ms)-U^(ms)-C^(e1p)-U^(ms)-C^(e1p)-A^(ms)-A^(ms)-C^(e1p)-A^(e1p)-G^(ms)-CH₂CH₂OH(III″-12) (SEQ ID NO: 37)HO-C^(e1p)-A^(ms)-T^(e1p)-A^(ms)-A^(ms)-T^(e1p)-G^(ms)-A^(ms)-A^(e1p)-A^(ms)-A^(ms)-C^(e1p)-G^(ms)-C^(ms)-C^(e1p)-G^(ms)-C^(e1p)-C^(e1p)-CH₂CH₂OH(III″-13) (SEQ ID NO: 30)HO-G^(ms)-A^(e2s)-A^(ms)-A^(ms)-A^(ms)-C^(e2s)-G^(ms)-C^(e2s)-C^(e2s)-G^(ms)-C^(ms)-C^(e2s)-A^(ms)-T^(e2s)-U^(ms)-U^(ms)-C^(e2s)-T^(e2s)-CH₂CH₂OH(III″-14) (SEQ ID NO: 36)HO-G^(ms)-C^(e2s)-C^(e2s)-G^(ms)-C^(e2s)-C^(ms)-A^(ms)-T^(e2s)-U^(ms)-U^(ms)-C^(e2s)-U^(ms)-C^(e2s)-A^(ms)-A^(ms)-C^(e2s)-A^(e2s)-G^(ms)-CH₂CH₂OH(III″-15) (SEQ ID NO: 37)HO-C^(e2s)-A^(ms)-T^(e2s)-A^(ms)-A^(ms)-T^(e2s)-G^(ms)-A^(ms)-A^(e2s)-A^(ms)-A^(ms)-C^(e2s)-G^(ms)-C^(ms)-C^(e2s)-G^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OH(III″-16) (SEQ ID NO: 30)HO-G^(ms)-A^(e1s)-A^(ms)-A^(ms)-A^(ms)-C^(e1s)-G^(ms)-C^(e1s)-C^(e1s)-G^(ms)-C^(ms)-C^(e1s)-A^(ms)-T^(e1s)-U^(ms)-U^(ms)-C^(e1s)-T^(e1s)-CH₂CH₂OH(III″-17) (SEQ ID NO: 36)HO-G^(ms)-C^(e1s)-C^(e1s)-G^(ms)-C^(e1s)-C^(ms)-A^(ms)-T^(e1s)-U^(ms)-U^(ms)-C^(e1s)-U^(ms)-C^(e1s)-A^(ms)-A^(ms)-C^(e1s)-A^(e1s)-G^(ms)-CH₂CH₂OH(III″-18) (SEQ ID NO: 37)HO-C^(e1s)-A^(ms)-T^(e1s)-A^(ms)-A^(ms)-T^(e1s)-G^(ms)-A^(ms)-A^(e1s)-A^(ms)-A^(ms)-C^(e1s)-G^(ms)-C^(ms)-C^(e1s)-G^(ms)-C^(e1s)-C^(e1s)-CH₂CH₂OHEspecially preferable are (III″-1), (III″-2), (III″-3), (III″-13),(III″-14) and (III″-15).

Preferable examples of the compound represented by general formula (IV″)include the following compounds.

(IV″-1) (SEQ ID NO: 43)HO-G^(mp)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-T^(e2p)-T^(e2p)-U^(mp)-G^(mp)-C^(e2p)-C^(mp)-C^(mp)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-CH₂CH₂OH(IV″-2) (SEQ ID NO: 46)HO-G^(mp)-C^(e2p)-T^(e2p)-A^(mp)-G^(mp)-G^(mp)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-T^(e2p)-T^(e2p)-U^(mp)-CH₂CH₂OH(IV″-3) (SEQ ID NO: 43)HO-G^(mp)-G^(mp)-C^(e1p)-T^(e1p)-G^(mp)-C^(mp)-T^(e1p)-T^(e1p)-U^(mp)-G^(mp)-C^(e1p)-C^(mp)-C^(mp)-T^(e1p)-C^(e1p)-A^(mp)-G^(mp)-C^(e1p)-CH₂CH₂OH(IV″-4) (SEQ ID NO: 46)HO-G^(mp)-C^(e1p)-T^(e1p)-A^(mp)-G^(mp)-G^(mp)-T^(e1p)-C^(e1p)-A^(mp)-G^(mp)-G^(mp)-C^(e1p)-T^(e1p)-G^(mp)-C^(mp)-T^(e1p)-T^(e1p)-U^(mp)-CH₂CH₂OH(IV″-5) (SEQ ID NO: 43)HO-G^(ms)-G^(ms)-C^(e2p)-T^(e2p)-G^(ms)-C^(ms)-T^(e2p)-T^(e2p)-U^(ms)-G^(ms)-C^(e2p)-C^(ms)-C^(ms)-T^(e2p)-C^(e2p)-A^(ms)-G^(ms)-C^(e2p)-CH₂CH₂OH(IV″-6) (SEQ ID NO: 46)HO-G^(ms)-C^(e2p)-T^(e2p)-A^(ms)-G^(ms)-G^(ms)-T^(e2p)-C^(e2p)-A^(ms)-G^(ms)-G^(ms)-C^(e2p)-T^(e2p)-G^(ms)-C^(ms)-T^(e2p)-T^(e2p)-U^(ms)-CH₂CH₂OH(IV″-7) (SEQ ID NO: 43)HO-G^(ms)-G^(ms)-C^(e1p)-T^(e1p)-G^(ms)-C^(ms)-T^(e1p)-T^(e1p)-U^(ms)-G^(ms)-C^(e1p)-C^(ms)-C^(ms)-T^(e1p)-C^(e1p)-A^(ms)-G^(ms)-C^(e1p)-CH₂CH₂OH(IV″-8) (SEQ ID NO: 46)HO-G^(ms)-C^(e1p)-T^(e1p)-A^(ms)-G^(ms)-G^(ms)-T^(e1p)-C^(e1p)-A^(ms)-G^(ms)-G^(ms)-C^(e1p)-T^(e1p)-G^(ms)-C^(ms)-T^(e1p)-T^(e1p)-U^(ms)-CH₂CH₂OH(IV″-9) (SEQ ID NO: 43)HO-G^(ms)-G^(ms)-C^(e2s)-T^(e2s)-G^(ms)-C^(ms)-T^(e2s)-T^(e2s)-U^(ms)-G^(ms)-C^(e2s)-C^(ms)-C^(ms)-T^(e2s)-C^(e2s)-A^(ms)-G^(ms)-C^(e2s)-CH₂CH₂OH(IV″-10) (SEQ ID NO: 46)HO-G^(ms)-C^(e2s)-T^(e2s)-A^(ms)-G^(ms)-G^(ms)-T^(e2s)-C^(e2s)-A^(ms)-G^(ms)-G^(ms)-C^(e2s)-T^(e2s)-G^(ms)-C^(ms)-T^(e2s)-T^(e2s)-U^(ms)-CH₂CH₂OH(IV″-11) (SEQ ID NO: 43)HO-G^(ms)-G^(ms)-C^(e1s)-T^(e1s)-G^(ms)-C^(ms)-T^(e1s)-T^(e1s)-U^(ms)-G^(ms)-C^(e1s)-C^(ms)-C^(ms)-T^(e1s)-C^(e1s)-A^(ms)-G^(ms)-C^(e1s)-CH₂CH₂OH(IV″-12) (SEQ ID NO: 46)HO-G^(ms)-C^(e1s)-T^(e1s)-A^(ms)-G^(ms)-G^(ms)-T^(e1s)-C^(e1s)-A^(ms)-G^(ms)-G^(ms)-C^(e1s)-T^(e1s)-G^(ms)-C^(ms)-T^(e1s)-T^(e1s)-U^(ms)-CH₂CH₂OHEspecially preferable are (IV″-1), (IV″-2), (IV″-9) and (IV″-10).

Preferable examples of the compound represented by general formula (V″)include the following compounds.

(V″-1) (SEQ ID NO: 44)HO-A^(mp)-G^(mp)-T^(e2p)-C^(e2p)-C^(e2p)-A^(mp)-G^(mp)-G^(mp)-A^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-A^(mp)-G^(mp)-G^(mp)-T^(e2p)-C^(e2p)-A^(mp)-CH₂CH₂OH(V″-2) (SEQ ID NO: 44)HO-A^(mp)-G^(mp)-T^(e1p)-C^(e1p)-C^(e1p)-A^(mp)-G^(mp)-G^(mp)-A^(e1p)-G^(mp)-C^(e1p)-T^(e1p)-A^(mp)-G^(mp)-G^(mp)-T^(e1p)-C^(e1p)-A^(mp)-CH₂CH₂OH(V″-3) (SEQ ID NO: 44)HO-A^(ms)-G^(ms)-T^(e2p)-C^(e2p)-C^(e2p)-A^(ms)-G^(ms)-G^(ms)-A^(e2p)-G^(ms)-C^(e2p)-T^(e2p)-A^(ms)-G^(ms)-G^(ms)-T^(e2p)-C^(e2p)-A^(ms)-CH₂CH₂OH(V″-4) (SEQ ID NO: 44)HO-A^(ms)-G^(ms)-T^(e1p)-C^(e1p)-C^(e1p)-A^(ms)-G^(ms)-G^(ms)-A^(e1p)-G^(ms)-C^(e1p)-T^(e1p)-A^(ms)-G^(ms)-G^(ms)-T^(e1p)-C^(e1p)-A^(ms)-CH₂CH₂OH(V″-5) (SEQ ID NO: 44)HO-A^(ms)-G^(ms)-T^(e2s)-C^(e2s)-C^(e2s)-A^(ms)-G^(ms)-G^(ms)-A^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-A^(ms)-G^(ms)-G^(ms)-T^(e2s)-C^(e2s)-A^(ms)-CH₂CH₂OH(V″-6) (SEQ ID NO: 44)HO-A^(ms)-G^(ms)-T^(e1s)-C^(e1s)-C^(e1s)-A^(ms)-G^(ms)-G^(ms)-A^(e1s)-G^(ms)-C^(e1s)-T^(e1s)-A^(ms)-G^(ms)-G^(ms)-T^(e1s)-C^(e1s)-A^(ms)-CH₂CH₂OHEspecially preferable are (V″-1) and (V″-5).

Preferable examples of the compound represented by general formula (VI″)include the following compounds.

(VI″-1) (SEQ ID NO: 47)HO-G^(mp)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-C^(e2p)-U^(mp)-C^(mp)-T^(e2p)-C^(mp)-G^(mp)-C^(e2p)-T^(e2p)-C^(mp)-A^(mp)-C^(e2p)-T^(e2p)-C^(mp)-CH₂CH₂OH(VI″-2) (SEQ ID NO: 48)HO-T^(e2p)-C^(e2p)-U^(mp)-U^(mp)-C^(e2p)-C^(e2p)-A^(mp)-A^(mp)-A^(mp)-G^(mp)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-C^(mp)-U^(mp)-C^(e2p)-T^(e2p)-CH₂CH₂OH(VI″-3) (SEQ ID NO: 47)HO-G^(mp)-C^(e1p)-A^(mp)-G^(mp)-C^(e1p)-C^(e1p)-U^(mp)-C^(mp)-T^(e1p)-C^(mp)-G^(mp)-C^(e1p)-T^(e1p)-C^(mp)-A^(mp)-C^(e1p)-T^(e1p)-C^(mp)-CH₂CH₂OH(VI″-4) (SEQ ID NO: 48)HO-T^(e1p)-C^(e1p)-U^(mp)-U^(mp)-C^(e1p)-C^(e1p)-A^(mp)-A^(mp)-A^(mp)-G^(mp)-C^(e1p)-A^(mp)-G^(mp)-C^(e1p)-C^(mp)-U^(mp)-C^(e1p)-T^(e1p)-CH₂CH₂OH(VI″-5) (SEQ ID NO: 47)HO-G^(ms)-C^(e2p)-A^(ms)-G^(ms)-C^(e2p)-C^(e2p)-U^(ms)-C^(ms)-T^(e2p)-C^(ms)-G^(ms)-C^(e2p)-T^(e2p)-C^(ms)-A^(ms)-C^(e2p)-T^(e2p)-C^(ms)-CH₂CH₂OH(VI″-6) (SEQ ID NO: 48)HO-T^(e2p)-C^(e2p)-U^(ms)-U^(ms)-C^(e2p)-C^(e2p)-A^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(e2p)-A^(ms)-G^(ms)-C^(e2p)-C^(ms)-U^(ms)-C^(e2p)-T^(e2p)-CH₂CH₂OH(VI″-7) (SEQ ID NO: 47)HO-G^(ms)-C^(e1p)-A^(ms)-G^(ms)-C^(e1p)-C^(e1p)-U^(ms)-C^(ms)-T^(e1p)-C^(ms)-G^(ms)-C^(e1p)-T^(e1p)-C^(ms)-A^(ms)-C^(e1p)-T^(e1p)-C^(ms)-CH₂CH₂OH(VI″-8) (SEQ ID NO: 48)HO-T^(e1p)-C^(e1p)-U^(ms)-U^(ms)-C^(e1p)-C^(e1p)-A^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(e1p)-A^(ms)-G^(ms)-C^(e1p)-C^(ms)-U^(ms)-C^(e1p)-T^(e1p)-CH₂CH₂OH(VI″-9) (SEQ ID NO: 47)HO-G^(ms)-C^(e2s)-A^(ms)-G^(ms)-C^(e2s)-C^(e2s)-U^(ms)-C^(ms)-T^(e2s)-C^(ms)-G^(ms)-C^(e2s)-T^(e2s)-C^(ms)-A^(ms)-C^(e2s)-T^(e2s)-C^(ms)-CH₂CH₂OH(VI″-10) (SEQ ID NO: 48)HO-T^(e2s)-C^(e2s)-U^(ms)-U^(ms)-C^(e2s)-C^(e2s)-A^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(e2s)-A^(ms)-G^(ms)-C^(e2s)-C^(ms)-U^(ms)-C^(e2s)-T^(e2s)-CH₂CH₂OH(VI″-11) (SEQ ID NO: 47)HO-G^(ms)-C^(e1s)-A^(ms)-G^(ms)-C^(e1s)-C^(e1s)-U^(ms)-C^(ms)-T^(e1s)-C^(ms)-G^(ms)-C^(e1s)-T^(e1s)-C^(ms)-A^(ms)-C^(e1s)-T^(e1s)-C^(ms)-CH₂CH₂OH(VI″-12) (SEQ ID NO: 48)HO-T^(e1s)-C^(e1s)-U^(ms)-U^(ms)-C^(e1s)-C^(e1s)-A^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(e1s)-A^(ms)-G^(ms)-C^(e1s)-C^(ms)-U^(ms)-C^(e1s)-T^(e1s)-CH₂CH₂OHEspecially preferable are (VI″-1), (VI″-2), (VI″-9) and (VI″-10).

Preferable examples of the compound represented by general formula(VII″) include the following compounds.

(VII″-1) (SEQ ID NO: 55)HO-C^(mp)-T^(e2p)-A^(mp)-T^(e2p)-G^(mp)-A^(mp)-G^(mp)-T^(e2p)-T^(e2p)-T^(e2p)-C^(mp)-T^(e2p)-T^(e2p)-C^(mp)-C^(mp)-A^(mp)-A^(e2p)-A^(mp)-CH₂CH₂OH(VII″-2) (SEQ ID NO: 55)HO-C^(mp)-T^(e1p)-A^(mp)-T^(e1p)-G^(mp)-A^(mp)-G^(mp)-T^(e1p)-T^(e1p)-T^(e1p)-C^(mp)-T^(e1p)-T^(e1p)-C^(mp)-C^(mp)-A^(mp)-A^(e1p)-A^(mp)-CH₂CH₂OH(VII″-3) (SEQ ID NO: 55)HO-C^(ms)-T^(e2p)-A^(ms)-T^(e2p)-G^(ms)-A^(ms)-G^(ms)-T^(e2p)-T^(e2p)-T^(e2p)-C^(ms)-T^(e2p)-T^(e2p)-C^(ms)-C^(ms)-A^(ms)-A^(e2p)-A^(ms)-CH₂CH₂OH(VII″-4) (SEQ ID NO: 55)HO-C^(ms)-T^(e1p)-A^(ms)-T^(e1p)-G^(ms)-A^(ms)-G^(ms)-T^(e1p)-T^(e1p)-T^(e1p)-C^(ms)-T^(e1p)-T^(e1p)-C^(ms)-C^(ms)-A^(ms)-A^(e1p)-A^(ms)-CH₂CH₂OH(VII″-5) (SEQ ID NO: 55)HO-C^(ms)-T^(e2s)-A^(ms)-T^(e2s)-G^(ms)-A^(ms)-G^(ms)-T^(e2s)-T^(e2s)-T^(e2s)-C^(ms)-T^(e2s)-T^(e2s)-C^(ms)-C^(ms)-A^(ms)-A^(e2s)-A^(ms)-CH₂CH₂OH(VII″-6) (SEQ ID NO: 55)HO-C^(ms)-T^(e1s)-A^(ms)-T^(e1s)-G^(ms)-A^(ms)-G^(ms)-T^(e1s)-T^(e1s)-T^(e1s)-C^(ms)-T^(e1s)-T^(e1s)-C^(ms)-C^(ms)-A^(ms)-A^(e1s)-A^(ms)-CH₂CH₂OHEspecially preferable are (VII″-1) and (VII″-5).

Preferable examples of the compound represented by general formula(VIII″) include the following compounds.

(VIII″-1) (SEQ ID NO: 53)HO-A^(mp)-G^(mp)-C^(e2p)-T^(e2p)-C^(mp)-U^(mp)-T^(e2p)-U^(mp)-T^(e2p)-A^(mp)-C^(mp)-T^(e2p)-C^(e2p)-C^(mp)-C^(mp)-T^(e2p)-T^(e2p)-G^(mp)-CH₂CH₂OH(VIII″-2) (SEQ ID NO: 54)HO-C^(e2p)-C^(e2p)-A^(mp)-U^(mp)-T^(e2p)-G^(mp)-U^(mp)-T^(e2p)-U^(mp)-C^(e2p)-A^(mp)-U^(mp)-C^(e2p)-A^(mp)-G^(mp)-C^(mp)-T^(e2p)-C^(e2p)-CH₂CH₂OH(VIII″-3) (SEQ ID NO: 53)HO-A^(mp)-G^(mp)-C^(e1p)-T^(e1p)-C^(mp)-U^(mp)-T^(e1p)-U^(mp)-T^(e1p)-A^(mp)-C^(mp)-T^(e1p)-C^(e1p)-C^(mp)-C^(mp)-T^(e1p)-T^(e1p)-G^(mp)-CH₂CH₂OH(VIII″-4) (SEQ ID NO: 54)HO-C^(e1p)-C^(e1p)-A^(mp)-U^(mp)-T^(e1p)-G^(mp)-U^(mp)-T^(e1p)-U^(mp)-C^(e1p)-A^(mp)-U^(mp)-C^(e1p)-A^(mp)-G^(mp)-C^(mp)-T^(e1p)-C^(e1p)-CH₂CH₂OH(VIII″-5) (SEQ ID NO: 53)HO-A^(ms)-G^(ms)-C^(e2p)-T^(e2p)-C^(ms)-U^(ms)-T^(e2p)-U^(ms)-T^(e2p)-A^(ms)-C^(ms)-T^(e2p)-C^(e2p)-C^(ms)-C^(ms)-T^(e2p)-T^(e2p)-G^(ms)-CH₂CH₂OH(VIII″-6) (SEQ ID NO: 54)HO-C^(e2p)-C^(e2p)-A^(ms)-U^(ms)-T^(e2p)-G^(ms)-U^(ms)-T^(e2p)-U^(ms)-C^(e2p)-A^(ms)-U^(ms)-C^(e2p)-A^(ms)-G^(ms)-C^(ms)-T^(e2p)-C^(e2p)-CH₂CH₂OH(VIII″-7) (SEQ ID NO: 53)HO-A^(ms)-G^(ms)-C^(e1p)-T^(e1p)-C^(ms)-U^(ms)-T^(e1p)-U^(ms)-T^(e1p)-A^(ms)-C^(ms)-T^(e1p)-C^(e1p)-C^(ms)-C^(ms)-T^(e1p)-T^(e1p)-G^(ms)-CH₂CH₂OH(VIII″-8) (SEQ ID NO: 54)HO-C^(e1p)-C^(e1p)-A^(ms)-U^(ms)-T^(e1p)-G^(ms)-U^(ms)-T^(e1p)-U^(ms)-C^(e1p)-A^(ms)-U^(ms)-C^(e1p)-A^(ms)-G^(ms)-C^(ms)-T^(e1p)-C^(e1p)-CH₂CH₂OH(VIII″-9) (SEQ ID NO: 53)HO-A^(ms)-G^(ms)-C^(e2s)-T^(e2s)-C^(ms)-U^(ms)-T^(e2s)-U^(ms)-T^(e2s)-A^(ms)-C^(ms)-T^(e2s)-C^(e2s)-C^(ms)-C^(ms)-T^(e2s)-T^(e2s)-G^(ms)-CH₂CH₂OH(VIII″-10) (SEQ ID NO: 54)HO-C^(e2s)-C^(e2s)-A^(ms)-U^(ms)-T^(e2s)-G^(ms)-U^(ms)-T^(e2s)-U^(ms)-C^(e2s)-A^(ms)-U^(ms)-C^(e2s)-A^(ms)-G^(ms)-C^(ms)-T^(e2s)-C^(e2s)-CH₂CH₂OH(VIII″-11) (SEQ ID NO: 53)HO-A^(ms)-G^(ms)-C^(e1s)-T^(e1s)-C^(ms)-U^(ms)-T^(e1s)-U^(ms)-T^(e1s)-A^(ms)-C^(ms)-T^(e1s)-C^(e1s)-C^(ms)-C^(ms)-T^(e1s)-T^(e1s)-G^(ms)-CH₂CH₂OH(VIII″-12) (SEQ ID NO: 54)HO-C^(e1s)-C^(e1s)-A^(ms)-U^(ms)-T^(e1s)-G^(ms)-U^(ms)-T^(e1s)-U^(ms)-C^(e1s)-A^(ms)-U^(ms)-C^(e1s)-A^(ms)-G^(ms)-C^(ms)-T^(e1s)-C^(e1s)-CH₂CH₂OHEspecially preferable are (VIII″-1), (VIII″-2), (VIII″-9) and(VIII″-10).

Preferable examples of the compound represented by general formula (IX″)include the following compounds.

(IX″-1) (SEQ ID NO: 63)HO-T^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-A^(e2p)-G^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(e2p)-G^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-CH₂CH₂OH(IX″-2) (SEQ ID NO: 56)Ph-T^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-T^(e2p)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(mp)-A^(e2p)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-CH₂CH₂OH (IX″-3) (SEQ ID NO: 56)HO-T^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-T^(e2p)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(mp)-A^(e2p)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-CH₂CH₂OH (IX″-4) (SEQ ID NO: 63)HO-T^(e1p)-A^(e1p)-A^(e1p)-C^(e1p)-A^(e1p)-G^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(e1p)-G^(e1p)-G^(e1p)-A^(e1p)-G^(e1p)-CH₂CH₂OH(IX″-5) (SEQ ID NO: 56)Ph-T^(e1p)-G^(e1p)-T^(e1p)-G^(e1p)-T^(e1p)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(mp)-A^(e1p)-C^(e1p)-A^(e1p)-G^(e1p)-T^(e1p)-CH₂CH₂OH (IX″-6) (SEQ ID NO: 56)HO-T^(e1p)-G^(e1p)-T^(e1p)-G^(e1p)-T^(e1p)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(mp)-A^(e1p)-C^(e1p)-A^(e1p)-G^(e1p)-T^(e1p)-CH₂CH₂OH (IX″-7) (SEQ ID NO: 63)HO-T^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-A^(e2p)-G^(ms)-U^(ms)-C^(ms)-U^(ms)-G^(ms)-A^(ms)-G^(ms)-U^(ms)-A^(e2p)-G^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-CH₂CH₂OH(IX″-8) (SEQ ID NO: 56)Ph-T^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-T^(e2p)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(ms)-G^(ms)-U^(ms)-A^(ms)-A^(e2p)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-CH₂CH₂OH (IX″-9) (SEQ ID NO: 56)HO-T^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-T^(e2p)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(ms)-G^(ms)-U^(ms)-A^(ms)-A^(e2p)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-CH₂CH₂OH (IX″-10) (SEQ ID NO: 63)HO-T^(e1p)-A^(e1p)-A^(e1p)-C^(e1p)-A^(e1p)-G^(ms)-U^(ms)-C^(ms)-U^(ms)-G^(ms)-A^(ms)-G^(ms)-U^(ms)-A^(e1p)-G^(e1p)-G^(e1p)-A^(e1p)-G^(e1p)-CH₂CH₂OH(IX″-11) (SEQ ID NO: 56)Ph-T^(e1p)-G^(e1p)-T^(e1p)-G^(e1p)-T^(e1p)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(ms)-G^(ms)-U^(ms)-A^(ms)-A^(e1p)-C^(e1p)-A^(e1p)-G^(e1p)-T^(e1p)-CH₂CH₂OH (IX″-12) (SEQ ID NO: 56)HO-T^(e1p)-G^(e1p)-T^(e1p)-G^(e1p)-T^(e1p)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(ms)-G^(ms)-U^(ms)-A^(ms)-A^(e1p)-C^(e1p)-A^(e1p)-G^(e1p)-T^(e1p)-CH₂CH₂OH (IX″-13) (SEQ ID NO: 63)HO-T^(e2s)-A^(e2s)-A^(e2s)-C^(e2s)-A^(e2s)-G^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(e2s)-G^(e2s)-G^(e2s)-A^(e2s)-G^(e2s)-CH₂CH₂OH(IX″-14) (SEQ ID NO: 56)Ph-T^(e2s)-G^(e2s)-T^(e2s)-G^(e2s)-T^(e2s)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(mp)-A^(e2s)-C^(e2s)-A^(e2s)-G^(e2s)-T^(e2s)-CH₂CH₂OH (IX″-15) (SEQ ID NO: 56)HO-T^(e2s)-G^(e2s)-T^(e2s)-G^(e2s)-T^(e2s)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(mp)-A^(e2s)-C^(e2s)-A^(e2s)-G^(e2s)-T^(e2s)-CH₂CH₂OH (IX″-16) (SEQ ID NO: 63)HO-T^(e1s)-A^(e1s)-A^(e1s)-C^(e1s)-A^(e1s)-G^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(e1s)-G^(e1s)-G^(e1s)-A^(e1s)-G^(e1s)-CH₂CH₂OH(IX″-17) (SEQ ID NO: 56)Ph-T^(e1s)-G^(e1s)-T^(e1s)-G^(e1s)-T^(e1s)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(mp)-A^(e1s)-C^(e1s)-A^(e1s)-G^(e1s)-T^(e1s)-CH₂CH₂OH (IX″-18) (SEQ ID NO: 56)HO-T^(e1s)-G^(e1s)-T^(e1s)-G^(e1s)-T^(e1s)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(mp)-A^(e1s)-C^(e1s)-A^(e1s)-G^(e1s)-T^(e1s)-CH₂CH₂OHEspecially preferable are (IX″-1), (IX″-2), (IX″-3), (IX″-13), (IX″-14)and (IX″-15).

Preferable examples of the compound represented by general formula (X″)include the following compounds.

(X″-1) (SEQ ID NO: 57)Ph-A^(e2p)-G^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(mp)-U^(mp)-G^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(e2p)-G^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-CH₂CH₂OH (X″-2) (SEQ ID NO: 57)HO-A^(e2p)-G^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(mp)-U^(mp)-G^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(e2p)-G^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-CH₂CH₂OH (X″-3) (SEQ ID NO: 57)Ph-A^(e1p)-G^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-G^(mp)-U^(mp)-G^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(e1p)-G^(e1p)-T^(e1p)-A^(e1p)-A^(e1p)-CH₂CH₂OH (X″-4) (SEQ ID NO: 57)HO-A^(e1p)-G^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-G^(mp)-U^(mp)-G^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(e1p)-G^(e1p)-T^(e1p)-A^(e1p)-A^(e1p)-CH₂CH₂OH (X″-5) (SEQ ID NO: 57)Ph-A^(e2p)-G^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(ms)-U^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(e2p)-G^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-CH₂CH₂OH (X″-6) (SEQ ID NO: 57)HO-A^(e2p)-G^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(ms)-U^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(e2p)-G^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-CH₂CH₂OH (X″-7) (SEQ ID NO: 57)Ph-A^(e1p)-G^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-G^(ms)-U^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(e1p)-G^(e1p)-T^(e1p)-A^(e1p)-A^(e1p)-CH₂CH₂OH (X″-8) (SEQ ID NO: 57)HO-A^(e1p)-G^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-G^(ms)-U^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(e1p)-G^(e1p)-T^(e1p)-A^(e1p)-A^(e1p)-CH₂CH₂OH (X″-9) (SEQ ID NO: 57)Ph-A^(e2s)-G^(e2s)-G^(e2s)-T^(e2s)-T^(e2s)-G^(ms)-U^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(e2s)-G^(e2s)-T^(e2s)-A^(e2s)-A^(e2s)-CH₂CH₂OH (X″-10) (SEQ ID NO: 57)HO-A^(e2s)-G^(e2s)-G^(e2s)-T^(e2s)-T^(e2s)-G^(ms)-U^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(e2s)-G^(e2s)-T^(e2s)-A^(e2s)-A^(e2s)-CH₂CH₂OH (X″-11) (SEQ ID NO: 57)Ph-A^(e1s)-G^(e1s)-G^(e1s)-T^(e1s)-T^(e1s)-G^(ms)-U^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(e1s)-G^(e1s)-T^(e1s)-A^(e1s)-A^(e1s)-CH₂CH₂OH (X″-12) (SEQ ID NO: 57)HO-A^(e1s)-G^(e1s)-G^(e1s)-T^(e1s)-T^(e1s)-G^(ms)-U^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(e1s)-G^(e1s)-T^(e1s)-A^(e1s)-A^(e1s)-CH₂CH₂OHEspecially preferable are (X″-1), (X″-2), (X″-9) and (X′-10).

Preferable examples of the compound represented by general formula (XI″)include the following compounds.

(XI″-1) (SEQ ID NO: 58)Ph-A^(e2p)-G^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-C^(mp)-C^(mp)-A^(mp)-C^(mp)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-U^(mp)-G^(mp)-T^(e2p)-G^(e2p)-T^(e2p)-C^(e2p)-A^(e2p)-CH₂CH₂OH (XI″-2) (SEQ ID NO: 58)HO-A^(e2p)-G^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-C^(mp)-C^(mp)-A^(mp)-C^(mp)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-U^(mp)-G^(mp)-T^(e2p)-G^(e2p)-T^(e2p)-C^(e2p)-A^(e2p)-CH₂CH₂OH (XI″-3) (SEQ ID NO: 58)Ph-A^(e1p)-G^(e1p)-T^(e1p)-A^(e1p)-A^(e1p)-C^(mp)-C^(mp)-A^(mp)-C^(mp)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-U^(mp)-G^(mp)-T^(e1p)-G^(e1p)-T^(e1p)-C^(e1p)-A^(e1p)-CH₂CH₂OH (XI″-4) (SEQ ID NO: 58)HO-A^(e1p)-G^(e1p)-T^(e1p)-A^(e1p)-A^(e1p)-C^(mp)-C^(mp)-A^(mp)-C^(mp)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-U^(mp)-G^(mp)-T^(e1p)-G^(e1p)-T^(e1p)-C^(e1p)-A^(e1p)-CH₂CH₂OH (XI″-5) (SEQ ID NO: 58)Ph-A^(e2p)-G^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-C^(ms)-C^(ms)-A^(ms)-C^(ms)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(ms)-T^(e2p)-G^(e2p)-T^(e2p)-C^(e2p)-A^(e2p)-CH₂CH₂OH (XI″-6) (SEQ ID NO: 58)HO-A^(e2p)-G^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-C^(ms)-C^(ms)-A^(ms)-C^(ms)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(ms)-T^(e2p)-G^(e2p)-T^(e2p)-C^(e2p)-A^(e2p)-CH₂CH₂OH (XI″-7) (SEQ ID NO: 58)Ph-A^(e1p)-G^(e1p)-T^(e1p)-A^(e1p)-A^(e1p)-C^(ms)-C^(ms)-A^(ms)-C^(ms)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(ms)-T^(e1p)-G^(e1p)-T^(e1p)-C^(e1p)-A^(e1p)-CH₂CH₂OH (XI″-8) (SEQ ID NO: 58)HO-A^(e1p)-G^(e1p)-T^(e1p)-A^(e1p)-A^(e1p)-C^(ms)-C^(ms)-A^(ms)-C^(ms)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(ms)-T^(e1p)-G^(e1p)-T^(e1p)-C^(e1p)-A^(e1p)-CH₂CH₂OH (XI″-9) (SEQ ID NO: 58)Ph-A^(e2s)-G^(e2s)-T^(e2s)-A^(e2s)-A^(e2s)-C^(ms)-C^(ms)-A^(ms)-C^(ms)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(ms)-T^(e2s)-G^(e2s)-T^(e2s)-C^(e2s)-A^(e2s)-CH₂CH₂OH (XI″-10) (SEQ ID NO: 58)HO-A^(e2s)-G^(e2s)-T^(e2s)-A^(e2s)-A^(e2s)-C^(ms)-C^(ms)-A^(ms)-C^(ms)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(ms)-T^(e2s)-G^(e2s)-T^(e2s)-C^(e2s)-A^(e2s)-CH₂CH₂OH (XI″-11) (SEQ ID NO: 58)Ph-A^(e1s)-G^(e1s)-T^(e1s)-A^(e1s)-A^(e1s)-C^(ms)-C^(ms)-A^(ms)-C^(ms)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(ms)-T^(e1s)-G^(e1s)-T^(e1s)-C^(e1s)-A^(e1s)-CH₂CH₂OH (XI″-12) (SEQ ID NO: 58)HO-A^(e1s)-G^(e1s)-T^(e1s)-A^(e1s)-A^(e1s)-C^(ms)-C^(ms)-A^(ms)-C^(ms)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-U^(ms)-G^(ms)-T^(e1s)-G^(e1s)-T^(e1s)-C^(e1s)-A^(e1s)-CH₂CH₂OHEspecially preferable are (XI″-1), (XI″-2), (XI″-9) and (XI″-10).

Preferable examples of the compound represented by general formula(XII″) include the following compounds.

(XII″-1) (SEQ ID NO: 60)Ph-C^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-C^(e2p)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-U^(mp)-U^(mp)-T^(e2p)-A^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-CH₂CH₂OH (XII″-2) (SEQ ID NO: 61)Ph-A^(e2p)-C^(e2p)-C^(e2p)-C^(e2p)-A^(e2p)-C^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-C^(mp)-U^(mp)-C^(e2p)-T^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-CH₂CH₂OH (XII″-3) (SEQ ID NO: 60)HO-C^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-C^(e2p)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-U^(mp)-U^(mp)-T^(e2p)-A^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-CH₂CH₂OH (XII″-4) (SEQ ID NO: 61)HO-A^(e2p)-C^(e2p)-C^(e2p)-C^(e2p)-A^(e2p)-C^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-C^(mp)-U^(mp)-C^(e2p)-T^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-CH₂CH₂OH (XII″-5) (SEQ ID NO: 60)Ph-C^(e1p)-A^(e1p)-C^(e1p)-C^(e1p)-C^(e1p)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-U^(mp)-U^(mp)-T^(e1p)-A^(e1p)-T^(e1p)-A^(e1p)-A^(e1p)-CH₂CH₂OH (XII″-6) (SEQ ID NO: 61)Ph-A^(e1p)-C^(e1p)-C^(e1p)-C^(e1p)-A^(e1p)-C^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-C^(mp)-U^(mp)-C^(e1p)-T^(e1p)-G^(e1p)-T^(e1p)-G^(e1p)-CH₂CH₂OH (XII″-7) (SEQ ID NO: 60)HO-C^(e1p)-A^(e1p)-C^(e1p)-C^(e1p)-C^(e1p)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-U^(mp)-U^(mp)-T^(e1p)-A^(e1p)-T^(e1p)-A^(e1p)-A^(e1p)-CH₂CH₂OH (XII″-8) (SEQ ID NO: 61)HO-A^(e1p)-C^(e1p)-C^(e1p)-C^(e1p)-A^(e1p)-C^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-C^(mp)-U^(mp)-C^(e1p)-T^(e1p)-G^(e1p)-T^(e1p)-G^(e1p)-CH₂CH₂OH (XII″-9) (SEQ ID NO: 60)Ph-C^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-C^(e2p)-U^(ms)-C^(ms)-U^(ms)-G^(ms)-U^(ms)-G^(ms)-A^(ms)-U^(ms)-U^(ms)-U^(ms)-T^(e2p)-A^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-CH₂CH₂OH (XII″-10) (SEQ ID NO: 61)Ph-A^(e2p)-C^(e2p)-C^(e2p)-C^(e2p)-A^(e2p)-C^(ms)-C^(ms)-A^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(e2p)-T^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-CH₂CH₂OH (XII″-11) (SEQ ID NO: 60)HO-C^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-C^(e2p)-U^(ms)-C^(ms)-U^(ms)-G^(ms)-U^(ms)-G^(ms)-A^(ms)-U^(ms)-U^(ms)-U^(ms)-T^(e2p)-A^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-CH₂CH₂OH (XII″-12) (SEQ ID NO: 61)HO-A^(e2p)-C^(e2p)-C^(e2p)-C^(e2p)-A^(e2p)-C^(ms)-C^(ms)-A^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(e2p)-T^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-CH₂CH₂OH (XII″-13) (SEQ ID NO: 60)Ph-C^(e1p)-A^(e1p)-C^(e1p)-C^(e1p)-C^(e1p)-U^(ms)-C^(ms)-U^(ms)-G^(ms)-U^(ms)-G^(ms)-A^(ms)-U^(ms)-U^(ms)-U^(ms)-T^(e1p)-A^(e1p)-T^(e1p)-A^(e1p)-A^(e1p)-CH₂CH₂OH (XII″-14) (SEQ ID NO: 61)Ph-A^(e1p)-C^(e1p)-C^(e1p)-C^(e1p)-A^(e1p)-C^(ms)-C^(ms)-A^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(e1p)-T^(e1p)-G^(e1p)-T^(e1p)-G^(e1p)-CH₂CH₂OH (XII″-15) (SEQ ID NO: 60)HO-C^(e1p)-A^(e1p)-C^(e1p)-C^(e1p)-C^(e1p)-U^(ms)-C^(ms)-U^(ms)-G^(ms)-U^(ms)-G^(ms)-A^(ms)-U^(ms)-U^(ms)-U^(ms)-T^(e1p)-A^(e1p)-T^(e1p)-A^(e1p)-A^(e1p)-CH₂CH₂OH (XII″-16) (SEQ ID NO: 61)HO-A^(e1p)-C^(e1p)-C^(e1p)-C^(e1p)-A^(e1p)-C^(ms)-C^(ms)-A^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(e1p)-T^(e1p)-G^(e1p)-T^(e1p)-G^(e1p)-CH₂CH₂OH (XII″-17) (SEQ ID NO: 60)Ph-C^(e2s)-A^(e2s)-C^(e2s)-C^(e2s)-C^(e2s)-U^(ms)-C^(ms)-U^(ms)-G^(ms)-U^(ms)-G^(ms)-A^(ms)-U^(ms)-U^(ms)-U^(ms)-T^(e2s)-A^(e2s)-T^(e2s)-A^(e2s)-A^(e2s)-CH₂CH₂OH (XII″-18) (SEQ ID NO: 61)Ph-A^(e2s)-C^(e2s)-C^(e2s)-C^(e2s)-A^(e2s)-C^(ms)-C^(ms)-A^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(e2s)-T^(e2s)-G^(e2s)-T^(e2s)-G^(e2s)-CH₂CH₂OH (XII″-19) (SEQ ID NO: 60)HO-C^(e2s)-A^(e2s)-C^(e2s)-C^(e2s)-C^(e2s)-U^(ms)-C^(ms)-U^(ms)-G^(ms)-U^(ms)-G^(ms)-A^(ms)-U^(ms)-U^(ms)-U^(ms)-T^(e2s)-A^(e2s)-T^(e2s)-A^(e2s)-A^(e2s)-CH₂CH₂OH (XII″-20) (SEQ ID NO: 61)HO-A^(e2s)-C^(e2s)-C^(e2s)-C^(e2s)-A^(e2s)-C^(ms)-C^(ms)-A^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(e2s)-T^(e2s)-G^(e2s)-T^(e2s)-G^(e2s)-CH₂CH₂OH (XII″-21) (SEQ ID NO: 60)Ph-C^(e1s)-A^(e1s)-C^(e1s)-C^(e1s)-C^(e1s)-U^(ms)-C^(ms)-U^(ms)-G^(ms)-U^(ms)-G^(ms)-A^(ms)-U^(ms)-U^(ms)-U^(ms)-T^(e1s)-A^(e1s)-T^(e1s)-A^(e1s)-A^(e1s)-CH₂CH₂OH (XII″-22) (SEQ ID NO: 61)Ph-A^(e1s)-C^(e1s)-C^(e1s)-C^(e1s)-A^(e1s)-C^(ms)-C^(ms)-A^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(e1s)-T^(e1s)-G^(e1s)-T^(e1s)-G^(e1s)-CH₂CH₂OH (XII″-23) (SEQ ID NO: 60)HO-C^(e1s)-A^(e1s)-C^(e1s)-C^(e1s)-C^(e1s)-U^(ms)-C^(ms)-U^(ms)-G^(ms)-U^(ms)-G^(ms)-A^(ms)-U^(ms)-U^(ms)-U^(ms)-T^(e1s)-A^(e1s)-T^(e1s)-A^(e1s)-A^(e1s)-CH₂CH₂OH (XII″-24) (SEQ ID NO: 61)HO-A^(e1s)-C^(e1s)-C^(e1s)-C^(e1s)-A^(e1s)-C^(ms)-C^(ms)-A^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(e1s)-T^(e1s)-G^(e1s)-T^(e1s)-G^(e1s)-CH₂CH₂OHEspecially preferable are (XII″-1), (XII″-2), (XII″-3), (XII″-4),(XII″-17), (XII″-18), (XII″-19) and (XII″-20).

Preferable examples of the compound represented by general formula(XIII″) include the following compounds.

(XIII″-1) (SEQ ID NO: 62)Ph-C^(e2p)-C^(e2p)-T^(e2p)-C^(e2p)-A^(e2p)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-C^(mp)-A^(mp)-C^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-CH₂CH₂OH (XIII″-2) (SEQ ID NO: 62)HO-C^(e2p)-C^(e2p)-T^(e2p)-C^(e2p)-A^(e2p)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-C^(mp)-A^(mp)-C^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-CH₂CH₂OH (XIII″-3) (SEQ ID NO: 62)Ph-C^(e1p)-C^(e1p)-T^(e1p)-C^(e1p)-A^(e1p)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-C^(mp)-A^(mp)-C^(e1p)-C^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-CH₂CH₂OH (XIII″-4) (SEQ ID NO: 62)HO-C^(e1p)-C^(e1p)-T^(e1p)-C^(e1p)-A^(e1p)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-C^(mp)-A^(mp)-C^(e1p)-C^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-CH₂CH₂OH (XIII″-5) (SEQ ID NO: 62)Ph-C^(e2p)-C^(e2p)-T^(e2p)-C^(e2p)-A^(e2p)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-A^(ms)-C^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-CH₂CH₂OH (XIII″-6) (SEQ ID NO: 62)HO-C^(e2p)-C^(e2p)-T^(e2p)-C^(e2p)-A^(e2p)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-A^(ms)-C^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-CH₂CH₂OH (XIII″-7) (SEQ ID NO: 62)Ph-C^(e1p)-C^(e1p)-T^(e1p)-C^(e1p)-A^(e1p)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-A^(ms)-C^(e1p)-C^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-CH₂CH₂OH (XIII″-8) (SEQ ID NO: 62)HO-C^(e1p)-C^(e1p)-T^(e1p)-C^(e1p)-A^(e1p)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-A^(ms)-C^(e1p)-C^(e1p)-A^(e1p)-T^(e1p)-C^(e1p)-CH₂CH₂OH (XIII″-9) (SEQ ID NO: 62)Ph-C^(e2s)-C^(e2s)-T^(e2s)-C^(e2s)-A^(e2s)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-A^(ms)-C^(e2s)-C^(e2s)-A^(e2s)-T^(e2s)-C^(e2s)-CH₂CH₂OH (XIII″-10) (SEQ ID NO: 62)HO-C^(e2s)-C^(e2s)-T^(e2s)-C^(e2s)-A^(e2s)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-A^(ms)-C^(e2s)-C^(e2s)-A^(e2s)-T^(e2s)-C^(e2s)-CH₂CH₂OH (XIII″-11) (SEQ ID NO: 62)Ph-C^(e1s)-C^(e1s)-T^(e1s)-C^(e1s)-A^(e1s)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-A^(ms)-C^(e1s)-C^(e1s)-A^(e1s)-T^(e1s)-C^(e1s)-CH₂CH₂OH (XIII″-12) (SEQ ID NO: 62)HO-C^(e1s)-C^(e1s)-T^(e1s)-C^(e1s)-A^(e1s)-A^(ms)-G^(ms)-G^(ms)-U^(ms)-C^(ms)-A^(ms)-C^(ms)-C^(ms)-C^(ms)-A^(ms)-C^(e1s)-C^(e1s)-A^(e1s)-T^(e1s)-C^(e1s)-CH₂CH₂OHEspecially preferable are (XIII″-1), (XIII″-2), (XIII″-9) and(XIII″-10).

Preferable examples of the compound represented by general formula(XIV″) include the following compounds.

(XIV″-1) (SEQ ID NO: 59)Ph-T^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-T^(e2p)-C^(mp)-A^(mp)-A^(mp)-G^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-A^(mp)-A^(e2p)-A^(e2p)-G^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH (XIV″-2) (SEQ ID NO: 59)HO-T^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-T^(e2p)-C^(mp)-A^(mp)-A^(mp)-G^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-A^(mp)-A^(e2p)-A^(e2p)-G^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH (XIV″-3) (SEQ ID NO: 65)HO-A^(e2p)-G^(e2p)-C^(e2p)-C^(e2p)-A^(e2p)-G^(mp)-U^(mp)-C^(mp)-G^(mp)-G^(mp)-U^(mp)-A^(mp)-A^(mp)-G^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH (XIV″-4) (SEQ ID NO: 59)Ph-T^(e1p)-T^(e1p)-G^(e1p)-A^(e1p)-T^(e1p)-C^(mp)-A^(mp)-A^(mp)-G^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-A^(mp)-A^(e1p)-A^(e1p)-G^(e1p)-C^(e1p)-C^(e1p)-CH₂CH₂OH (XIV″-5) (SEQ ID NO: 59)HO-T^(e1p)-T^(e1p)-G^(e1p)-A^(e1p)-T^(e1p)-C^(mp)-A^(mp)-A^(mp)-G^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-A^(mp)-A^(e1p)-A^(e1p)-G^(e1p)-C^(e1p)-C^(e1p)-CH₂CH₂OH (XIV″-6) (SEQ ID NO: 65)HO-A^(e1p)-G^(e1p)-C^(e1p)-C^(e1p)-A^(e1p)-G^(mp)-U^(mp)-C^(mp)-G^(mp)-G^(mp)-U^(mp)-A^(mp)-A^(mp)-G^(e1p)-T^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-CH₂CH₂OH (XIV″-7) (SEQ ID NO: 59)Ph-T^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-T^(e2p)-C^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(ms)-G^(ms)-A^(ms)-A^(e2p)-A^(e2p)-G^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH (XIV″-8) (SEQ ID NO: 59)HO-T^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-T^(e2p)-C^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(ms)-G^(ms)-A^(ms)-A^(e2p)-A^(e2p)-G^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH (XIV″-9) (SEQ ID NO: 65)HO-A^(e2p)-G^(e2p)-C^(e2p)-C^(e2p)-A^(e2p)-G^(ms)-U^(ms)-C^(ms)-G^(ms)-G^(ms)-U^(ms)-A^(ms)-A^(ms)-G^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH (XIV″-10) (SEQ ID NO: 59)Ph-T^(e1p)-T^(e1p)-G^(e1p)-A^(e1p)-T^(e1p)-C^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(ms)-G^(ms)-A^(ms)-A^(e1p)-A^(e1p)-G^(e1p)-C^(e1p)-C^(e1p)-CH₂CH₂OH (XIV″-11) (SEQ ID NO: 59)HO-T^(e1p)-T^(e1p)-G^(e1p)-A^(e1p)-T^(e1p)-C^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(ms)-G^(ms)-A^(ms)-A^(e1p)-A^(e1p)-G^(e1p)-C^(e1p)-C^(e1p)-CH₂CH₂OH (XIV″-12) (SEQ ID NO: 65)HO-A^(e1p)-G^(e1p)-C^(e1p)-C^(e1p)-A^(e1p)-G^(ms)-U^(ms)-C^(ms)-G^(ms)-G^(ms)-U^(ms)-A^(ms)-A^(ms)-G^(e1p)-T^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-CH₂CH₂OH (XIV″-13) (SEQ ID NO: 59)Ph-T^(e2s)-T^(e2s)-G^(e2s)-A^(e2s)-T^(e2s)-C^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(ms)-G^(ms)-A^(ms)-A^(e2s)-A^(e2s)-G^(e2s)-C^(e2s)-C^(e2s)-CH₂CH₂OH (XIV″-14) (SEQ ID NO: 59)HO-T^(e2s)-T^(e2s)-G^(e2s)-A^(e2s)-T^(e2s)-C^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(ms)-G^(ms)-A^(ms)-A^(e2s)-A^(e2s)-G^(e2s)-C^(e2s)-C^(e2s)-CH₂CH₂OH (XIV″-15) (SEQ ID NO: 65)HO-A^(e2s)-G^(e2s)-C^(e2s)-C^(e2s)-A^(e2s)-G^(ms)-U^(ms)-C^(ms)-G^(ms)-G^(ms)-U^(ms)-A^(ms)-A^(ms)-G^(e2s)-T^(e2s)-T^(e2s)-C^(e2s)-T^(e2s)-CH₂CH₂OH (XIV″-16) (SEQ ID NO: 59)Ph-T^(e1s)-T^(e1s)-G^(e1s)-A^(e1s)-T^(e1s)-C^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(ms)-G^(ms)-A^(ms)-A^(e1s)-A^(e1s)-G^(e1s)-C^(e1s)-C^(e1s)-CH₂CH₂OH (XIV″-17) (SEQ ID NO: 59)HO-T^(e1s)-T^(e1s)-G^(e1s)-A^(e1s)-T^(e1s)-C^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(ms)-A^(ms)-G^(ms)-A^(ms)-G^(ms)-A^(ms)-A^(e1s)-A^(e1s)-G^(e1s)-C^(e1s)-C^(e1s)-CH₂CH₂OH (XIV″-18) (SEQ ID NO: 65)HO-A^(e1s)-G^(e1s)-C^(e1s)-C^(e1s)-A^(e1s)-G^(ms)-U^(ms)-C^(ms)-G^(ms)-G^(ms)-U^(ms)-A^(ms)-A^(ms)-G^(e1s)-T^(e1s)-T^(e1s)-C^(e1s)-T^(e1s)-CH₂CH₂OHEspecially preferable are (XIV″-1), (XIV″-2), (XIV″-3), (XIV″-13),(XIV″-14) and (XIV″-15).

Preferable examples of the compound represented by general formula (XV″)include the following compounds.

(XV″-1) (SEQ ID NO: 64)HO-G^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-U^(mp)-U^(mp)-C^(mp)-U^(mp)-A^(mp)-G^(mp)-U^(mp)-U^(mp)-T^(e2p)-G^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-CH₂CH₂OH (XV″-2) (SEQ ID NO: 66)HO-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-T^(e2p)-G^(mp)-G^(mp)-A^(mp)-G^(mp)-A^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-CH₂CH₂OH (XV″-3) (SEQ ID NO: 87)HO-G^(mp)-G^(mp)-C^(e2p)-A^(mp)-T^(e2p)-T^(e2p)-U^(mp)-C^(e2p)-T^(e2p)-A^(mp)-G^(mp)-U^(mp)-T^(e2p)-T^(e2p)-G^(mp)-G^(mp)-A^(e2p)-G^(mp)-CH₂CH₂OH (XV″-4) (SEQ ID NO: 88)HO-A^(e2p)-G^(mp)-T^(e2p)-U^(mp)-T^(e2p)-G^(mp)-G^(mp)-A^(e2p)-G^(mp)-A^(mp)-T^(e2p)-G^(mp)-G^(mp)-C^(e2p)-A^(e2p)-G^(mp)-T^(e2p)-T^(e2p)-CH₂CH₂OH (XV″-5) (SEQ ID NO: 64)HO-G^(e1p)-G^(e1p)-C^(e1p)-A^(e1p)-T^(e1p)-U^(mp)-U^(mp)-C^(mp)-U^(mp)-A^(mp)-G^(mp)-U^(mp)-U^(mp)-T^(e1p)-G^(e1p)-G^(e1p)-A^(e1p)-G^(e1p)-CH₂CH₂OH (XV″-6) (SEQ ID NO: 66)HO-A^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-T^(e1p)-G^(mp)-G^(mp)-A^(mp)-G^(mp)-A^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(e1p)-A^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-CH₂CH₂OH (XV″-7) (SEQ ID NO: 87)HO-G^(mp)-G^(mp)-C^(e1p)-A^(mp)-T^(e1p)-T^(e1p)-U^(mp)-C^(e1p)-T^(e1p)-A^(mp)-G^(mp)-U^(mp)-T^(e1p)-T^(e1p)-G^(mp)-G^(mp)-A^(e1p)-G^(mp)-CH₂CH₂OH (XV″-8) (SEQ ID NO: 88)HO-A^(e1p)-G^(mp)-T^(e1p)-U^(mp)-T^(e1p)-G^(mp)-G^(mp)-A^(e1p)-G^(mp)-A^(mp)-T^(e1p)-G^(mp)-G^(mp)-C^(e1p)-A^(e1p)-G^(mp)-T^(e1p)-T^(e1p)-CH₂CH₂OH (XV″-9) (SEQ ID NO: 64)HO-G^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-U^(ms)-U^(ms)-C^(ms)-U^(ms)-A^(ms)-G^(ms)-U^(ms)-U^(ms)-T^(e2p)-G^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-CH₂CH₂OH (XV″-10) (SEQ ID NO: 66)HO-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-T^(e2p)-G^(ms)-G^(ms)-A^(ms)-G^(ms)-A^(ms)-U^(ms)-G^(ms)-G^(ms)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-CH₂CH₂OH (XV″-11) (SEQ ID NO: 87)HO-G^(ms)-G^(ms)-C^(e2p)-A^(ms)-T^(e2p)-T^(e2p)-U^(ms)-C^(e2p)-T^(e2p)-A^(ms)-G^(ms)-U^(ms)-T^(e2p)-T^(e2p)-G^(ms)-G^(ms)-A^(e2p)-G^(ms)-CH₂CH₂OH (XV″-12) (SEQ ID NO: 88)HO-A^(e2p)-G^(ms)-T^(e2p)-U^(ms)-T^(e2p)-G^(ms)-G^(ms)-A^(e2p)-G^(ms)-A^(ms)-T^(e2p)-G^(ms)-G^(ms)-C^(e2p)-A^(e2p)-G^(ms)-T^(e2p)-T^(e2p)-CH₂CH₂OH (XV″-13) (SEQ ID NO: 64)HO-G^(e1p)-G^(e1p)-C^(e1p)-A^(e1p)-T^(e1p)-U^(ms)-U^(ms)-C^(ms)-U^(ms)-A^(ms)-G^(ms)-U^(ms)-U^(ms)-T^(e1p)-G^(e1p)-G^(e1p)-A^(e1p)-G^(e1p)-CH₂CH₂OH (XV″-14) (SEQ ID NO: 66)HO-A^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-T^(e1p)-G^(ms)-G^(ms)-A^(ms)-G^(ms)-A^(ms)-U^(ms)-G^(ms)-G^(ms)-C^(e1p)-A^(e1p)-G^(e1p)-T^(e1p)-T^(e1p)-CH₂CH₂OH (XV″-15) (SEQ ID NO: 87)HO-G^(ms)-G^(ms)-C^(e1p)-A^(ms)-T^(e1p)-T^(e1p)-U^(ms)-C^(e1p)-T^(e1p)-A^(ms)-G^(ms)-U^(ms)-T^(e1p)-T^(e1p)-G^(ms)-G^(ms)-A^(e1p)-G^(ms)-CH₂CH₂OH (XV″-16) (SEQ ID NO: 88)HO-A^(e1p)-G^(ms)-T^(e1p)-U^(ms)-T^(e1p)-G^(ms)-G^(ms)-A^(e1p)-G^(ms)-A^(ms)-T^(e1p)-G^(ms)-G^(ms)-C^(e1p)-A^(e1p)-G^(ms)-T^(e1p)-T^(e1p)-CH₂CH₂OH (XV″-17) (SEQ ID NO: 64)HO-G^(e2s)-G^(e2s)-C^(e2s)-A^(e2s)-T^(e2s)-U^(ms)-U^(ms)-C^(ms)-U^(ms)-A^(ms)-G^(ms)-U^(ms)-U^(ms)-T^(e2s)-G^(e2s)-G^(e2s)-A^(e2s)-G^(e2s)-CH₂CH₂OH (XV″-18) (SEQ ID NO: 66)HO-A^(e2s)-G^(e2s)-T^(e2s)-T^(e2s)-T^(e2s)-G^(ms)-G^(ms)-A^(ms)-G^(ms)-A^(ms)-U^(ms)-G^(ms)-G^(ms)-C^(e2s)-A^(e2s)-G^(e2s)-T^(e2s)-T^(e2s)-CH₂CH₂OH (XV″-19) (SEQ ID NO: 87)HO-G^(ms)-G^(ms)-C^(e2s)-A^(ms)-T^(e2s)-T^(e2s)-U^(ms)-C^(e2s)-T^(e2s)-A^(ms)-G^(ms)-U^(ms)-T^(e2s)-T^(e2s)-G^(ms)-G^(ms)-A^(e2s)-G^(ms)-CH₂CH₂OH (XV″-20) (SEQ ID NO: 88)HO-A^(e2s)-G^(ms)-T^(e2s)-U^(ms)-T^(e2s)-G^(ms)-G^(ms)-A^(e2s)-G^(ms)-A^(ms)-T^(e2s)-G^(ms)-G^(ms)-C^(e2s)-A^(e2s)-G^(ms)-T^(e2s)-T^(e2s)-CH₂CH₂OH (XV″-21) (SEQ ID NO: 64)HO-G^(e1s)-G^(e1s)-C^(e1s)-A^(e1s)-T^(e1s)-U^(ms)-U^(ms)-C^(ms)-U^(ms)-A^(ms)-G^(ms)-U^(ms)-U^(ms)-T^(e1s)-G^(e1s)-G^(e1s)-A^(e1s)-G^(e1s)-CH₂CH₂OH (XV″-22) (SEQ ID NO: 66)HO-A^(e1s)-G^(e1s)-T^(e1s)-T^(e1s)-T^(e1s)-G^(ms)-G^(ms)-A^(ms)-G^(ms)-A^(ms)-U^(ms)-G^(ms)-G^(ms)-C^(e1s)-A^(e1s)-G^(e1s)-T^(e1s)-T^(e1s)-CH₂CH₂OH (XV″-23) (SEQ ID NO: 87)HO-G^(ms)-G^(ms)-C^(e1s)-A^(ms)-T^(e1s)-T^(e1s)-U^(ms)-C^(e1s)-T^(e1s)-A^(ms)-G^(ms)-U^(ms)-T^(e1s)-T^(e1s)-G^(ms)-G^(ms)-A^(e1s)-G^(ms)-CH₂CH₂OH (XV″-24) (SEQ ID NO: 88)HO-A^(e1s)-G^(ms)-T^(e1s)-U^(ms)-T^(e1s)-G^(ms)-G^(ms)-A^(e1s)-G^(ms)-A^(ms)-T^(e1s)-G^(ms)-G^(ms)-C^(e1s)-A^(e1s)-G^(ms)-T^(e1s)-T^(e1s)-CH₂CH₂OHEspecially preferable are (XV″-1), (XV″-2), (XV″-3), (XV″-4), (XV″-17),(XV″-18), (XV″-19) and (XV″-20).

Preferable examples of the compound represented by general formula(XVI″) include the following compounds.

(XVI″-1) (SEQ ID NO: 68)HO-T^(e2p)-T^(e2p)-C^(mp)-T^(e2p)-T^(e2p)-G^(mp)-T^(e2p)-A^(mp)-C^(mp)-T^(e2p)-T^(e2p)-C^(mp)-A^(mp)-T^(e2p)-C^(mp)-C^(e2p)-C^(e2p)-A^(mp)-CH₂CH₂OH (XVI″-2) (SEQ ID NO: 75)HO-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-A^(mp)-G^(mp)-G^(mp)-T^(e2p)-G^(mp)-T^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-G^(mp)-T^(e2p)-A^(mp)-C^(e2p)-CH₂CH₂OH (XVI″-3) (SEQ ID NO: 68)HO-T^(e1p)-T^(e1p)-C^(mp)-T^(e1p)-T^(e1p)-G^(mp)-T^(e1p)-A^(mp)-C^(mp)-T^(e1p)-T^(e1p)-C^(mp)-A^(mp)-T^(e1p)-C^(mp)-C^(e1p)-C^(e1p)-A^(mp)-CH₂CH₂OH (XVI″-4) (SEQ ID NO: 75)HO-C^(e1p)-T^(e1p)-G^(mp)-A^(mp)-A^(mp)-G^(mp)-G^(mp)-T^(e1p)-G^(mp)-T^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-T^(e1p)-G^(mp)-T^(e1p)-A^(mp)-C^(e1p)-CH₂CH₂OH (XVI″-5) (SEQ ID NO: 68)HO-T^(e2p)-T^(e2p)-C^(ms)-T^(e2p)-T^(e2p)-G^(ms)-T^(e2p)-A^(ms)-C^(ms)-T^(e2p)-T^(e2p)-C^(ms)-A^(ms)-T^(e2p)-C^(ms)-C^(e2p)-C^(e2p)-A^(ms)-CH₂CH₂OH (XVI″-6) (SEQ ID NO: 75)HO-C^(e2p)-T^(e2p)-G^(ms)-A^(ms)-A^(ms)-G^(ms)-G^(ms)-T^(e2p)-G^(ms)-T^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-G^(ms)-T^(e2p)-A^(ms)-C^(e2p)-CH₂CH₂OH (XVI″-7) (SEQ ID NO: 68)HO-T^(e1p)-T^(e1p)-C^(ms)-T^(e1p)-T^(e1p)-G^(ms)-T^(e1p)-A^(ms)-C^(ms)-T^(e1p)-T^(e1p)-C^(ms)-A^(ms)-T^(e1p)-C^(ms)-C^(e1p)-C^(e1p)-A^(ms)-CH₂CH₂OH (XVI″-8) (SEQ ID NO: 75)HO-C^(e1p)-T^(e1p)-G^(ms)-A^(ms)-A^(ms)-G^(ms)-G^(ms)-T^(e1p)-G^(ms)-T^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-T^(e1p)-G^(ms)-T^(e1p)-A^(ms)-C^(e1p)-CH₂CH₂OH (XVI″-9) (SEQ ID NO: 68)HO-T^(e2s)-T^(e2s)-C^(ms)-T^(e2s)-T^(e2s)-G^(ms)-T^(e2s)-A^(ms)-C^(ms)-T^(e2s)-T^(e2s)-C^(ms)-A^(ms)-T^(e2s)-C^(ms)-C^(e2s)-C^(e2s)-A^(ms)-CH₂CH₂OH (XVI″-10) (SEQ ID NO: 75)HO-C^(e2s)-T^(e2s)-G^(ms)-A^(ms)-A^(ms)-G^(ms)-G^(ms)-T^(e2s)-G^(ms)-T^(e2s)-T^(e2s)-C^(e2s)-T^(e2s)-T^(e2s)-G^(ms)-T^(e2s)-A^(ms)-C^(e2s)-CH₂CH₂OH (XVI″-11) (SEQ ID NO: 68)HO-T^(e1s)-T^(e1s)-C^(ms)-T^(e1s)-T^(e1s)-G^(ms)-T^(e1s)-A^(ms)-C^(ms)-T^(e1s)-T^(e1s)-C^(ms)-A^(ms)-T^(e1s)-C^(ms)-C^(e1s)-C^(e1s)-A^(ms)-CH₂CH₂OH (XVI″-12) (SEQ ID NO: 75)HO-C^(e1s)-T^(e1s)-G^(ms)-A^(ms)-A^(ms)-G^(ms)-G^(ms)-T^(e1s)-G^(ms)-T^(e1s)-T^(e1s)-C^(e1s)-T^(e1s)-T^(e1s)-G^(ms)-T^(e1s)-A^(ms)-C^(e1s)-CH₂CH₂OHEspecially preferable are (XVI″-1), (XVI″-2), (XVI″-9) and (XVI″-10).

Preferable examples of the compound represented by general formula(XVII″) include the following compounds.

(XVII″-1) (SEQ ID NO: 69)HO-C^(e2p)-C^(e2p)-U^(mp)-C^(e2p)-C^(e2p)-G^(mp)-G^(mp)-T^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-A^(mp)-G^(mp)-G^(mp)-T^(e2p)-G^(mp)-CH₂CH₂OH(XVII″-2) (SEQ ID NO: 69)HO-C^(e1p)-C^(e1p)-U^(mp)-C^(e1p)-C^(e1p)-G^(mp)-G^(mp)-T^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-G^(mp)-A^(mp)-A^(mp)-G^(mp)-G^(mp)-T^(e1p)-G^(mp)-CH₂CH₂OH(XVII″-3) (SEQ ID NO: 69)HO-C^(e2p)-C^(e2p)-U^(ms)-C^(e2p)-C^(e2p)-G^(ms)-G^(ms)-T^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(ms)-A^(ms)-A^(ms)-G^(ms)-G^(ms)-T^(e2p)-G^(ms)-CH₂CH₂OH(XVII″-4) (SEQ ID NO: 69)HO-C^(e1p)-C^(e1p)-U^(ms)-C^(e1p)-C^(e1p)-G^(ms)-G^(ms)-T^(e1p)-T^(e1p)-C^(e1p)-T^(e1p)-G^(ms)-A^(ms)-A^(ms)-G^(ms)-G^(ms)-T^(e1p)-G^(ms)-CH₂CH₂OH(XVII″-5) (SEQ ID NO: 69)HO-C^(e2s)-C^(e2s)-U^(ms)-C^(e2s)-C^(e2s)-G^(ms)-G^(ms)-T^(e2s)-T^(e2s)-C^(e2s)-T^(e2s)-G^(ms)-A^(ms)-A^(ms)-G^(ms)-G^(ms)-T^(e2s)-G^(ms)-CH₂CH₂OH(XVII″-6) (SEQ ID NO: 69)HO-C^(e1s)-C^(e1s)-U^(ms)-C^(e1s)-C^(e1s)-G^(ms)-G^(ms)-T^(e1s)-T^(e1s)-C^(e1s)-T^(e1s)-G^(ms)-A^(ms)-A^(ms)-G^(ms)-G^(ms)-T^(e1s)-G^(ms)-CH₂CH₂OHEspecially preferable are (XVII″-1) and (XVII″-5).

Preferable examples of the compound represented by general formula(XVIII″) include the following compounds.

(XVIII″-1) (SEQ ID NO: 72)HO-T^(e2p)-A^(mp)-A^(mp)-G^(mp)-A^(mp)-C^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-U^(mp)-T^(e2p)-C^(e2p)-CH₂CH₂OH(XVIII″-2) (SEQ ID NO: 77)HO-C^(e2p)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-T^(e2p)-U^(mp)-C^(mp)-T^(e2p)-T^(e2p)-C^(mp)-C^(mp)-T^(e2p)-T^(e2p)-A^(mp)-G^(mp)-C^(e2p)-CH₂CH₂OH(XVIII″-3) (SEQ ID NO: 72)HO-T^(e1p)-A^(mp)-A^(mp)-G^(mp)-A^(mp)-C^(e1p)-C^(e1p)-T^(e1p)-G^(mp)-C^(e1p)-T^(e1p)-C^(e1p)-A^(mp)-G^(mp)-C^(e1p)-U^(mp)-T^(e1p)-C^(e1p)-CH₂CH₂OH(XVIII″-4) (SEQ ID NO: 77)HO-C^(e1p)-T^(e1p)-C^(e1p)-A^(mp)-G^(mp)-C^(e1p)-T^(e1p)-U^(mp)-C^(mp)-T^(e1p)-T^(e1p)-C^(mp)-C^(mp)-T^(e1p)-T^(e1p)-A^(mp)-G^(mp)-C^(e1p)-CH₂CH₂OH(XVIII″-5) (SEQ ID NO: 72)HO-T^(e2p)-A^(ms)-A^(ms)-G^(ms)-A^(ms)-C^(e2p)-C^(e2p)-T^(e2p)-G^(ms)-C^(e2p)-T^(e2p)-C^(e2p)-A^(ms)-G^(ms)-C^(e2p)-U^(ms)-T^(e2p)-C^(e2p)-CH₂CH₂OH(XVIII″-6) (SEQ ID NO: 77)HO-C^(e2p)-T^(e2p)-C^(e2p)-A^(ms)-G^(ms)-C^(e2p)-T^(e2p)-U^(ms)-C^(ms)-T^(e2p)-T^(e2p)-C^(ms)-C^(ms)-T^(e2p)-T^(e2p)-A^(ms)-G^(ms)-C^(e2p)-CH₂CH₂OH(XVIII″-7) (SEQ ID NO: 72)HO-T^(e1p)-A^(ms)-A^(ms)-G^(ms)-A^(ms)-C^(e1p)-C^(e1p)-T^(e1p)-G^(ms)-C^(e1p)-T^(e1p)-C^(e1p)-A^(ms)-G^(ms)-C^(e1p)-U^(ms)-T^(e1p)-C^(e1p)-CH₂CH₂OH(XVIII″-8) (SEQ ID NO: 77)HO-C^(e1p)-T^(e1p)-C^(e1p)-A^(ms)-G^(ms)-C^(e1p)-T^(e1p)-U^(ms)-C^(ms)-T^(e1p)-T^(e1p)-C^(ms)-C^(ms)-T^(e1p)-T^(e1p)-A^(ms)-G^(ms)-C^(e1p)-CH₂CH₂OH(XVIII″-9) (SEQ ID NO: 72)HO-T^(e2s)-A^(ms)-A^(ms)-G^(ms)-A^(ms)-C^(e2s)-C^(e2s)-T^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-C^(e2s)-A^(ms)-G^(ms)-C^(e2s)-U^(ms)-T^(e2s)-C^(e2s)-CH₂CH₂OH(XVIII″-10) (SEQ ID NO: 77)HO-C^(e2s)-T^(e2s)-C^(e2s)-A^(ms)-G^(ms)-C^(e2s)-T^(e2s)-U^(ms)-C^(ms)-T^(e2s)-T^(e2s)-C^(ms)-C^(ms)-T^(e2s)-T^(e2s)-A^(ms)-G^(ms)-C^(e2s)-CH₂CH₂OH(XVIII″-11) (SEQ ID NO: 72)HO-T^(e1s)-A^(ms)-A^(ms)-G^(ms)-A^(ms)-C^(e1s)-C^(e1s)-T^(e1s)-G^(ms)-C^(e1s)-T^(e1s)-C^(e1s)-A^(ms)-G^(ms)-C^(e1s)-U^(ms)-T^(e1s)-C^(e1s)-CH₂CH₂OH(XVIII″-12) (SEQ ID NO: 77)HO-C^(e1s)-T^(e1s)-C^(e1s)-A^(ms)-G^(ms)-C^(e1s)-T^(e1s)-U^(ms)-C^(ms)-T^(e1s)-T^(e1s)-C^(ms)-C^(ms)-T^(e1s)-T^(e1s)-A^(ms)-G^(ms)-C^(e1s)-CH₂CH₂OHEspecially preferable are (XVIII″-1), (XVIII″-2), (XVIII″-9) and(XVIII″-10).

Preferable examples of the compound represented by general formula(XIX″) include the following compounds.

(XIX″-1) (SEQ ID NO: 76)HO-T^(e2p)-T^(e2p)-C^(mp)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-C^(e2p)-A^(mp)-T^(e2p)-T^(e2p)-G^(mp)-T^(e2p)-G^(mp)-T^(e2p)-T^(e2p)-G^(mp)-A^(mp)-CH₂CH₂OH(XIX″-2) (SEQ ID NO: 76)HO-T^(e1p)-T^(e1p)-C^(mp)-C^(e1p)-A^(mp)-G^(mp)-C^(e1p)-C^(e1p)-A^(mp)-T^(e1p)-T^(e1p)-G^(mp)-T^(e1p)-G^(mp)-T^(e1p)-T^(e1p)-G^(mp)-A^(mp)-CH₂CH₂OH(XIX″-3) (SEQ ID NO: 76)HO-T^(e2p)-T^(e2p)-C^(ms)-C^(e2p)-A^(ms)-G^(ms)-C^(e2p)-C^(e2p)-A^(ms)-T^(e2p)-T^(e2p)-G^(ms)-T^(e2p)-G^(ms)-T^(e2p)-T^(e2p)-G^(ms)-A^(ms)-CH₂CH₂OH(XIX″-4) (SEQ ID NO: 76)HO-T^(e1p)-T^(e1p)-C^(ms)-C^(e1p)-A^(ms)-G^(ms)-C^(e1p)-C^(e1p)-A^(ms)-T^(e1p)-T^(e1p)-G^(ms)-T^(e1p)-G^(ms)-T^(e1p)-T^(e1p)-G^(ms)-A^(ms)-CH₂CH₂OH(XIX″-5) (SEQ ID NO: 76)HO-T^(e2s)-T^(e2s)-C^(ms)-C^(e2s)-A^(ms)-G^(ms)-C^(e2s)-C^(e2s)-A^(ms)-T^(e2s)-T^(e2s)-G^(ms)-T^(e2s)-G^(ms)-T^(e2s)-T^(e2s)-G^(ms)-A^(ms)-CH₂CH₂OH(XIX″-6) (SEQ ID NO: 76)HO-T^(e1s)-T^(e1s)-C^(ms)-C^(e1s)-A^(ms)-G^(ms)-C^(e1s)-C^(e1s)-A^(ms)-T^(e1s)-T^(e1s)-G^(ms)-T^(e1s)-G^(ms)-T^(e1s)-T^(e1s)-G^(ms)-A^(ms)-CH₂CH₂OHEspecially preferable are (XIX″-1) and (XIX″-5).

Preferable examples of the compound represented by general formula (XX″)include the following compounds.

(XX″-1) (SEQ ID NO: 71)HO-T^(e2p)-T^(e2p)-C^(mp)-C^(mp)-T^(e2p)-T^(e2p)-A^(mp)-G^(mp)-C^(e2p)-T^(e2p)-U^(mp)-C^(e2p)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-C^(e2p)-A^(mp)-CH₂CH₂OH(XX″-2) (SEQ ID NO: 71)HO-T^(e1p)-T^(e1p)-C^(mp)-C^(mp)-T^(e1p)-T^(e1p)-A^(mp)-G^(mp)-C^(e1p)-T^(e1p)-U^(mp)-C^(e1p)-C^(e1p)-A^(mp)-G^(mp)-C^(e1p)-C^(e1p)-A^(mp)-CH₂CH₂OH(XX″-3) (SEQ ID NO: 71)HO-T^(e2p)-T^(e2p)-C^(ms)-C^(ms)-T^(e2p)-T^(e2p)-A^(ms)-G^(ms)-C^(e2p)-T^(e2p)-U^(ms)-C^(e2p)-C^(e2p)-A^(ms)-G^(ms)-C^(e2p)-C^(e2p)-A^(ms)-CH₂CH₂OH(XX″-4) (SEQ ID NO: 71)HO-T^(e1p)-T^(e1p)-C^(ms)-C^(ms)-T^(e1p)-T^(e1p)-A^(ms)-G^(ms)-C^(e1p)-T^(e1p)-U^(ms)-C^(e1p)-C^(e1p)-A^(ms)-G^(ms)-C^(e1p)-C^(e1p)-A^(ms)-CH₂CH₂OH(XX″-5) (SEQ ID NO: 71)HO-T^(e2s)-T^(e2s)-C^(ms)-C^(ms)-T^(e2s)-T^(e2s)-A^(ms)-G^(ms)-C^(e2s)-T^(e2s)-U^(ms)-C^(e2s)-C^(e2s)-A^(ms)-G^(ms)-C^(e2s)-C^(e2s)-A^(ms)-CH₂CH₂OH(XX″-6) (SEQ ID NO: 71)HO-T^(e1s)-T^(e1s)-C^(ms)-C^(ms)-T^(e1s)-T^(e1s)-A^(ms)-G^(ms)-C^(e1s)-T^(e1s)-U^(ms)-C^(e1s)-C^(e1s)-A^(ms)-G^(ms)-C^(e1s)-C^(e1s)-A^(ms)-CH₂CH₂OHEspecially preferable are (XX″-1) and (XX″-5).

Preferable examples of the compound represented by general formula(XXI″) include the following compounds.

(XXI″-1) (SEQ ID NO: 78)HO-G^(mp)-C^(e2p)-T^(e2p)-T^(e2p)-C^(mp)-U^(mp)-T^(e2p)-C^(e2p)-C^(mp)-U^(mp)-T^(e2p)-A^(mp)-G^(mp)-C^(e2p)-U^(mp)-T^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH(XXI″-2) (SEQ ID NO: 78)HO-G^(mp)-C^(e1p)-T^(e1p)-T^(e1p)-C^(mp)-U^(mp)-T^(e1p)-C^(e1p)-C^(mp)-U^(mp)-T^(e1p)-A^(mp)-G^(mp)-C^(e1p)-U^(mp)-T^(e1p)-C^(e1p)-C^(e1p)-CH₂CH₂OH(XXI″-3) (SEQ ID NO: 78)HO-G^(ms)-C^(e2p)-T^(e2p)-T^(e2p)-C^(ms)-U^(ms)-T^(e2p)-C^(e2p)-C^(ms)-U^(ms)-T^(e2p)-A^(ms)-G^(ms)-C^(e2p)-U^(ms)-T^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH(XXI″-4) (SEQ ID NO: 78)HO-G^(ms)-C^(e1p)-T^(e1p)-T^(e1p)-C^(ms)-U^(ms)-T^(e1p)-C^(e1p)-C^(ms)-U^(ms)-T^(e1p)-A^(ms)-G^(ms)-C^(e1p)-U^(ms)-T^(e1p)-C^(e1p)-C^(e1p)-CH₂CH₂OH(XXI″-5) (SEQ ID NO: 78)HO-G^(ms)-C^(e2s)-T^(e2s)-T^(e2s)-C^(ms)-U^(ms)-T^(e2s)-C^(e2s)-C^(ms)-U^(ms)-T^(e2s)-A^(ms)-G^(ms)-C^(e2s)-U^(ms)-T^(e2s)-C^(e2s)-C^(e2s)-CH₂CH₂OH(XXI″-6) (SEQ ID NO: 78)HO-G^(ms)-C^(e1s)-T^(e1s)-T^(e1s)-C^(ms)-U^(ms)-T^(e1s)-C^(e1s)-C^(ms)-U^(ms)-T^(e1s)-A^(ms)-G^(ms)-C^(e1s)-U^(ms)-T^(e1s)-C^(e1s)-C^(e1s)-CH₂CH₂OHEspecially preferable are (XXI″-1) and (XXI″-5).

In the present specification, A^(e1p), G^(e1p), C^(e1p), T^(e1p),A^(e2p), G^(e2p), C^(e2p), T^(a2p), A^(mp), G^(mp), C^(mp), U^(mp),A^(e1s), G^(e1s), C^(e1s), T^(e1s), A^(e2s), G^(e2s), C^(e2s), T^(e2s),A^(ms), G^(ms), C^(mS), U^(ms) and Ph are groups having the followingstructures, respectively.

The term “pharmacologically acceptable salt thereof” used in the presentspecification refers to salts of the oligonucleotide of the invention(e.g. oligonucleotide having the nucleotide sequence as shown in any oneof SEQ ID NOS: 1-6, 10-22, 30-78, 87 or 88) or salts of those compoundsrepresented by general formulas (I), (I′) to (VII′) and (I″) to (XXI″).Examples of such salts include metal salts such as alkali metal salts(e.g. sodium salts, potassium salts, lithium salts), alkaline earthmetal salts (e.g. calcium salts, magnesium salts), aluminium salts, ironsalts, zinc salts, copper salts, nickel salts, cobalt salts and thelike; amine salts such as inorganic salts (e.g. ammonium salts), organicsalts [e.g. t-octylamine salts, dibenzylamine salts, morpholine salts,glucosamine salts, phenylglycine alkyl ester salts, ethylenediaminesalts, N-methylglucamine salts, guanidine salts, diethylamine salts,triethylamine salts, dicyclohexylamine salts;N′,N′-dibenzylethylenediamine salts, chloroprocaine salts, procainesalts, diethanolamine salts, N-benzyl-phenetylamine salts, piperazinesalts, tetramethylammonium salts, tris(hydroxymethyl)aminomethane salts]and the like; inorganic acid salts such as halogenated hydroacid salts(e.g. hydrofluorates, hydrochlorides, hydrobromates, hydriodates),nitrates, perchlorates, sulfates, phosphates and the like; organic acidsalts such as lower alkane sulfonates (e.g. methanesulfonates,trifluoromethanesulfonates, ethanesulfonates), aryl sulfonates (e.g.benzensulfonates, p-toluenesulfonates), acetates, malates, fumarates,succinates, citrates, tartrates, oxalates, maleates and the like; andamino acid salts (e.g. glycine salts, lysine salts, arginine salts,ornithine salts, glutamates, aspartates). These salts may be preparedaccording to known methods.

It should be noted that compounds represented by general formulas (I),(I′) to (VII′) and (I″) to (XXI″) may occur as hydrates and that suchhydrates are also included in the present invention.

The oligonucleotide of the invention, the compounds represented bygeneral formulas (I), (I′) to (VII′) and (I″) to (XXI″) (hereinafter,referred to as the “compound of the invention”) and pharmacologicallyacceptable salts thereof are effective as pharmaceuticals for treatingmuscular dystrophy.

The compound of the invention may be synthesized based on the methoddescribed in the literature (Nucleic Acids Research, 12: 4539 (1984))using a commercial synthesizer (e.g. PerkinElmer Model 392 employing thephosphoroamidite method). As to the phosphoroamidite reagents used inthe synthesis, commercial reagents are available for natural nucleosidesand 2′-O-methylnucleosides (i.e. 2′-O-methylguanosine,2′-O-methyladenosine, 2′-O-methylcytosine and 2′-O-methyluridine). As to2′-O-alkyl-guanosine, -adenosine, -cytosine and -uridine where the alkylgroup has 2-6 carbon atoms, they may be synthesized or purchased asdescribed below.

2′-O-aminoethyl-guanosine, -adenosine, -cytosine and -uridine may besynthesized according to Blommers et al., Biochemistry (1998), 37:17714-17725.

2′-O-propyl-guanosine, -adenosine, -cytosine and -uridine may besynthesized according to Lesnik, E. A. et al., Biochemistry (1993), 32:7832-7838.

2′-O-allyl-guanosine, -adenosine, -cytosine and -uridine arecommercially available.

2′-O-methoxyethyl-guanosine, -adenosine, -cytosine and -uridine may besynthesized according to U.S. Pat. No. 6,261,840 or Martin, P., Helv.Chim. Acta. (1995) 78: 486-504.

2′-O-butyl-guanosine, -adenosine, -cytosine and -uridine may besynthesized according to Lesnik, E. A. et al., Biochemistry (1993), 32:7832-7838.

2′-O-pentyl-guanosine, -adenosine, -cytosine and -uridine may besynthesized according to Lesnik, E. A. et al., Biochemistry (1993), 32:7832-7838.

2′-O-propargyl-guanosine, -adenosine, -cytosine and -uridine arecommercially available.

2′-O,4′-C-methylene-guanosine, -adenosine, 5-methyl-cytosine and-thymidine may be synthesized according to the method described inWO99/14226. 2′-O,4′-C-alkylene-guanosine and -adenosine where thealkylene group has 2-5 carbon atoms, 5-methyl-cytosine and -thymidinemay be synthesized according to the method described in WO00/47599.

In the thioation of phosphate groups, thioate derivatives may beobtained based on the methods described in Tetrahedron Letters, 32, 3005(1991) and J. Am. Chem. Soc., 112, 1253 (1990), using sulfur and areagent such as tetraethylthiuram disulfide (TETD; Applied Biosystems)or Beaucage reagent (Glen Research) which reacts with a trivalentphosphate to form a thioate.

With respect to the controlled pore glass (DPG) used in the synthesizer,use of a modified CPG (described in Example 12b of Japanese UnexaminedPatent Publication No. H7-87982) allows synthesis of oligonucleotides towhich 2-hydroxyethylphosphate group is attached at the 3′ end. Further,use of 3′-amino-Modifier C3 CPG, 3′-amino-Modifier C7 CPG, Glyceryl CPG(Glen Research), 3′-specer C3 SynBase CPG 1000 or 3′-specer C9 SynBaseCPG 1000 (Link Technologies) allows synthesis of oligonucleotides towhich a hydroxyalkylphosphate group or aminoalkylphosphate group isattached at the 3′ end.

The compounds of the present invention and pharmacologically acceptablesalts thereof have an effect of inducing skipping of exon 19, 41, 45,46, 44, 50, 55, 51 or 53 of the dystrophin gene. The compounds of theinvention represented by general formulas (I), (I′) to (VII′) and (I″)to (XXI″) and pharmacologically acceptable salts thereof have highbinding strength to RNA and high resistance to nuclease. Therefore, thecompounds of the invention and pharmacologically acceptable saltsthereof are useful as pharmaceuticals for treating muscular dystrophy.

When the compound of the invention or a pharmacologically acceptablesalt thereof is used as a therapeutic for muscular dystrophy, thecompound or a pharmacologically acceptable salt or ester thereof may beadministered by itself. Alternatively, the compound or apharmacologically acceptable salt or ester thereof may be mixed withappropriate pharmacologically acceptable excipients or diluents,prepared into tablets, capsules, granules, powders, syrups, etc. andadministered orally; or prepared into injections, suppositories,patches, external medicines, etc. and administered parenterally.

These formulations may be prepared by well-known methods using additivessuch as excipients [organic excipients e.g. sugar derivatives (such aslactose, white sugar, glucose, mannitol and sorbitol), starchderivatives (such as corn starch, potato starch, α starch and dextrin),cellulose derivatives (such as crystalline cellulose), gum arabic,dextran, pullulan and the like; and inorganic excipients e.g. silicatederivatives (such as light silicic acid anhydride, synthetic aluminiumsilicate, calcium silicate and magnesium aluminate metasilicate),phosphates (such as calcium hydrogenphosphate), carbonates (such ascalcium carbonate), sulfates (such as calcium sulfate) and the like],lubricants (e.g. metal salts of stearic acid such as stearic acid,calcium stearate, and magnesium stearate; talc; colloidal silica; waxessuch as bees wax and spermaceti; boric acid; adipic acid; sulfates suchas sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine;lauryl sulfates such as sodium lauryl sulfate and magnesium laurylsulfate; silicic acid materials such as silicic acid anhydride andsilicic acid hydrate; above-mentioned starch derivatives), binders (e.g.hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, macrogol, compounds enumerated above asexcipients), disintegrants (e.g. cellulose derivatives such aslow-substituted hydroxypropylcellulose, carboxymethylcellulose, calciumcarboxymethylcellulose, internally crosslinked sodiumcarboxymethylcellulose; chemically modifies starches/celluloses such ascarboxymethyl starch, sodium carboxymethyl starch, crosslinkedpolyvinylpyrrolidone), emulsifiers (e.g. colloidal clay such asbentonite, Veegum; metal hydroxides such as magnesium hydroxide,aluminium hydroxide; anionic surfactants such as sodium lauryl sulfate,calcium stearate; cation surfactants such as benzalkonium chloride;nonionic surfactants such as polyoxyethylene alkyl ethers,polyoxyethylene sorbitan fatty acid esters, sucrose fatty acid ester),stabilizers (e.g. paraoxybenzoic acid esters such as methyl paraben,propyl paraben; alcohols such as chlorobutanol, benzyl alcohol,phenylethyl alcohol; benzalkonium chloride; phenols such as phenol,cresol; thimerosal; dehydroacetic acid; sorbic acid), flavoring/aromaticagents (e.g. conventionally used sweeteners, acidifiers, aromatics,etc.) or diluents.

The therapeutic agent of the present invention comprises preferably0.05-5 μmoles/ml of the compound of the invention or a pharmacologicallyacceptable salt thereof, 0.02-10% w/v of carbohydrates or polyhydricalcohols, and 0.01-0.4% w/v of pharmacologically acceptable surfactants.More preferable range for the content of the compound of the inventionor a pharmacologically acceptable salt thereof is 0.1-1 μmoles/ml.

For the above carbohydrates, monosaccharides and/or disaccharides areespecially preferable. Examples of these carbohydrates and polyhydricalcohols include, but are not limited to, glucose, galactose, mannose,lactose, maltose, mannitol and sorbitol. These may be used alone or incombination.

Preferable examples of surfactants include, but are not limited to,polyoxyethylene sorbitan mono- to tri-esters, alkyl phenylpolyoxyethylene, sodium taurocholate, sodium cholate and polyhydricalcohol esters. Especially preferable are polyoxyethylene sorbitan mono-to tri-esters, where especially preferable esters are oleates, laurates,stearates and palmitates. These surfactants may be used alone or incombination.

More preferably, the therapeutic agent of the invention comprises0.03-0.09 M of pharmacologically acceptable neutral salt, e.g. sodiumchloride, potassium chloride and/or calcium chloride.

Still more preferably, the therapeutic agent of the invention maycomprise 0.002-0.05 M of pharmacologically acceptable buffer. Examplesof preferable buffers include sodium citrate, sodium glycinate, sodiumphosphate and tris(hydroxymethyl)aminomethane. These buffers may be usedalone or in combination.

The above-described therapeutic agent of the invention may be suppliedin the state of solution. However, considering the storing of thetherapeutic agent for some period of time, usually, it is preferable tolyophilize the therapeutic agent for the purpose of stabilizing theantisense oligonucleotide and thereby preventing the lowering of itstherapeutic effect. The lyophilized therapeutic agent may bereconstructed with a dissolving liquid (e.g. distilled water forinjection) at the time of use, and used in the state of solution. Thus,the therapeutic agent of the invention encompasses such a lyophilizedtherapeutic agent to be reconstructed with a dissolving liquid at thetime of use so that individual components fall under specificconcentration ranges. In order to enhance the solubility of thelyophilized product, the therapeutic agent may further contain albuminor amino acids such as glycine.

When the compound of the invention or a pharmacologically acceptablesalt thereof is administered to humans, for example, the compound orsalt may be administered orally or intravenously at a dose of about0.1-100 mg/kg body weight per day, preferably 1-50 mg/kg body weight perday for adult patients once a day or divided into several portions. Thedose and the number of times of administration may be appropriatelychanged depending on the type of disease, conditions, the age of thepatient, the route of administration, etc.

Administration of the compound of the invention or a pharmacologicallyacceptable salt thereof to DMD patients may be performed, for example,as described below. Briefly, the compound of the invention or apharmacologically acceptable salt thereof may be prepared by methodswell-known to those skilled in the art, sterilized by conventionalmethods and then formulated into, for example, an injection solutionwith a concentration of 1200 μg/ml. This solution is, for example,drip-fed to the patient intravenously in the form of infusion so thatthe antisense oligonucleotide is administered to the patient at a doseof, for example, 20 mg/kg body weight. Such administration may berepeated, for example, 4 times at intervals of 2 weeks. Then, whileconfirming the therapeutic effect using indicators such as expression ofdystrophin protein in muscle biopsy tissues, serum creatine kinaselevels and clinical symptoms, this treatment is repeated appropriately.If therapeutic effect is recognized and yet no definite side effect isobserved, this treatment is continued; in principle, the administrationis continued throughout life time.

The present specification includes the contents disclosed in thespecifications and/or drawings of the Japanese Patent Applications No.2002-340857 and No. 2003-204381 based on which the present applicationclaims priority.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph of electrophoresis showing the results ofamplification of exons 17-20 by RT-PCR using RNAs extracted frommuscular cells transfected with the compound of Example 1 (AO1) and fromuntreated muscular cells.

FIG. 2 a photograph of electrophoresis showing the results ofamplification of exons 17-20 by RT-PCR using RNAs extracted frommuscular cells transfected with any one of the compounds of Examples 1-7(AO1, AO14, AO15, AO16, AO18, AO19 and AO25), 13 (AO17) and 14 (AO24)and from untreated muscular cells.

FIG. 3 a photograph of electrophoresis showing the results ofamplification of exons 17-20 by RT-PCR using RNAs extracted frommuscular cells transfected with any one of the compounds of Examples 5(AO18) and 8-12 (AO50, AO51, AO52, AO53 and AO54) and from untreatedmuscular cells.

FIG. 4 shows the effects of the compounds of Examples 15-19 (AO20, AO26,AO55, AO56 and AO57) on exon 41 skipping.

FIG. 5 shows the effects of the compounds of Examples 17-25 (AO55, AO56,AO57, AO76, AO77, AO78, AO79, AO80 and AO81) on exon 41 skipping.

FIG. 6 shows the effects of the compounds of Examples 26-29 (AO33, AO85,AO86 and AO87) on exon 45 skipping.

FIG. 7 shows the effects of the compounds of Examples 32-35 (AO23, AO27,AO28 and AO29) on exon 46 skipping.

FIG. 8 shows the effects of the compounds of Examples 33 and 36 (AO27and AO48) on exon 46 skipping.

FIG. 9 shows the effects of the compounds of Examples 31, 33 and 34 andthe compounds of Reference Examples 1-3 (AO2, AO27 and AO28; hAON4,hAON6 and hAON8) on exon 46 skipping.

FIG. 10 shows the effects of the compounds of Examples 42-47 (AO100,AO102, AO103, AO104, AO105 and AO106) on exon 44 skipping.

FIG. 11 shows the effects of the compounds of Examples 42, 62, 63, 47,64, 46 and 65 (AO100, AO124, AO125, AO106, AO126, AO105 and AO127) onexon 44 skipping.

FIG. 12 shows the effects of the compounds of Examples 48-53 (AO108,AO109, AO110, AO111, AO112 and AO113) on exon 50 skipping.

FIG. 13 shows the effects of the compounds of Examples 49, 51, 52 and 66(AO109, AO111, AO112 and AO128) on exon 50 skipping.

FIG. 14 shows the effects of the compounds of Examples 68-71 (AO3, AO4,AO5 and AO6) on exon 51 skipping.

FIG. 15 shows the effects of the compounds of Examples 72-74 (AO8, AO9and AO10) on exon 51 skipping.

FIG. 16 shows the effect of the compound of Example 75 (AO37) on exon 51skipping.

FIG. 17 shows the effects of the compounds of Examples 76-78 (AO39, AO43and AO58) on exon 51 skipping.

FIG. 18 shows the effects of the compounds of Examples 79-86 (AO64,AO65, AO66, AO67, AO69, AO70, AO71 and AO72) on exon 53 skipping.

FIG. 19 shows the effects of the compounds of Examples 87-90 (AO95,AO96, AO97 and AO98) on exon 53 skipping.

FIG. 20 shows the effects of the compounds of Examples 54-61 (AO114,AO115, AO116, AO118, AO119, AO120, AO122 and AO123) on exon 55 skipping.

FIG. 21 shows the effects of the compounds of Examples 54, 55 and 67(AO114, AO115 and AO129) on exon 55 skipping.

FIG. 22 shows the effects of the compounds of Examples 33, 37, 38, 39,40 and 41 (AO27, AO89, AO90, AO91, AO92 and AO93) on exon 46 skipping.

BEST MODES FOR CARRYING OUT THE INVENTION

Hereinbelow, the present invention will be described specifically withreference to the following Examples. These Examples are provided onlyfor the purpose of illustration, and they are not intended to limit thepresent invention.

Example 1 Synthesis ofHO-G^(e2p)-C^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-G^(mp)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-CH₂CH₂OH(AO1)(SEQ ID NO: 196)

The subject compound was synthesized with an automated nucleic acidsynthesizer (PerkinElmer ABI model 394 DNA/RNA synthesizer) at a 40 nmolscale. The concentrations of solvents, reagents and phosphoroamidites atindividual synthesis cycles were the same as used in the synthesis ofnatural oligonucleotides. The solvents, reagents and phosphoroamiditesof 2′-O-methylnucleoside (adenosine form: product No. 27-1822-41;guanosine form: product No. 27-1826-41; citydine form: product No.27-1823-02; uridine form: product No. 27-1825-42) were products fromAmersham Pharmacia. As non-natural phosphoroamidites, those compoundsdisclosed in Example 14(5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-6-N-benzoyladenosine-3′-O-(2-cyanoethylN,N-diisopropyl)phosphoroamidite), Example 27(5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-2-N-isobutylylguanosine-3′-O-(2-cyanoethylN,N-diisopropyl)phosphoroamidite), Example 22(5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-4-N-benzoyl-5-methylcitydine-3′-O-(2-cyanoethylN,N-diisopropyl)phosphoroamidite), and Example 9(5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-5-methyluridine-3′-O-(2-cyanoethylN,N-diisopropyl)phosphoroamidite) of Japanese Unexamined PatentPublication No. 2000-297097 were used. The subject compound wassynthesized on a modified control pore glass (CPG) (disclosed in Example12b of Japanese Unexamined Patent Publication No. H7-87982) as a solidsupport. However, the time period for condensation of amidites was 15min.

The protected oligonucleotide analogue having the sequence of interestwas treated with concentrated aqueous ammonia to thereby cut out theoligomer from the support and, at the same time, remove the protectivecyanoethyl groups on phosphorus atoms and the protective groups onnucleic acid bases. The solvent was distilled off under reducedpressure, and the resultant residue was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (10 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.06min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest. When analyzed by reversed phase HPLC [column: Merck,Chromolith Performance RP-18e (4.6×100 mm); solution A: 5% acetonitrile,0.1 M aqueous triethylamine acetate (TEAA), pH 7.0; solution B: 25%acetonitrile, 0.1 M TEAA B %: 15%→60% (10 min, linear gradient); 60° C.;2 ml/min; 254 nm], the subject compound was eluted at 9.61 min. (0.393A₂₆₀ units) (λmax (H₂O)=260 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 10628.04; measured value: 10626.86).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2571-2607 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 2 Synthesis ofHO-G_(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH(AO14)(SEQ ID NO: 197)

The compound of Example 2 having a sequence of interest was synthesizedin the same manner as in Example 1. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→45% (10 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.64 min was collected. Whenanalyzed by reversed phase HPLC [column: Merck, Chromolith PerformanceRP-18e (4.6×100 mm)); solution A: 5% acetonitrile, 0.1 M aqueoustriethylamine acetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1M TEAA B %: 15%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254nm], the subject compound was eluted at 4.58 min. (0.806 A₂₆₀ units)(λmax (H₂O)=261 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 5281.60; measured value: 5281.40).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2578-2592 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 3 Synthesis ofHO-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-G^(mp)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-CH₂CH₂OH(AO15)(SEQ ID NO: 198)

The compound of Example 3 having a sequence of interest was synthesizedin the same manner as in Example 1. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→45% (10 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.47 min was collected. Whenanalyzed by reversed phase HPLC [column: Merck, Chromolith PerformanceRP-18e (4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueoustriethylamine acetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1M TEAA B %: 15%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254nm], the subject compound was eluted at 7.38 min. (15.05 A₂₆₀ units)(λmax (H₂O)=259 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 7609.08; measured value: 7609.43).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2571-2592 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 4 Synthesis ofHO-G^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-T^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-A^(mp)-G^(e2p)-CH₂CH₂OH(AO16)(SEQ ID NO: 199)

The compound of Example 4 having a sequence of interest was synthesizedin the same manner as in Example 1. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→55% (10 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.23 min was collected. Whenanalyzed by reversed phase HPLC [column: Merck, Chromolith PerformanceRP-18e (4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueoustriethylamine acetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1M TEAA B %: 15%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254nm], the subject compound was eluted at 6.34 min. (6.13 A₂₆₀ units)(λmax (H₂O)=259.4 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 6968.69; measured value: 6969.14).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2573-2592 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 5 Synthesis ofHO-A^(mp)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(mp)-T^(e2p)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(e2p)-C^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH(AO18)(SEQ ID NO: 200)

The compound of Example 5 having a sequence of interest was synthesizedin the same manner as in Example 1. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→46% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 5.39 min was collected. Whenanalyzed by reversed phase HPLC [column: Merck, Chromolith PerformanceRP-18e (4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueoustriethylamine acetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1M TEAA B %: 15%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254nm], the subject compound was eluted at 5.22 min. (6.88 A₂₆₀ units)(λmax (H₂O)=261 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 6623.48; measured value: 6623.68).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2578-2596 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 6 Synthesis ofHO-G^(e2p)-C^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(e2p)-C^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH(AO19)(SEQ ID NO: 201)

The compound of Example 6 having a sequence of interest was synthesizedin the same manner as in Example 1. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→46% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 5.10 min was collected. Whenanalyzed by reversed phase HPLC [column: Merck, Chromolith PerformanceRP-18e (4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueoustriethylamine acetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1M TEAA B %: 15%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254nm], the subject compound was eluted at 7.07 min. (6.98 A₂₆₀ units)(λmax (H₂O)=259 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 8300.57; measured value: 8300.14).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2578-2601 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 7 Synthesis ofHO-A^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH(AO25)(SEQ ID NO: 4)

The compound of Example 7 having a sequence of interest was synthesizedin the same manner as in Example 1. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→46% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 4.71 min was collected. Whenanalyzed by reversed phase HPLC [column: Merck, Chromolith PerformanceRP-18e (4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueoustriethylamine acetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1M TEAA B %: 15%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254nm], the subject compound was eluted at 8.75 min. (5.26 A₂₆₀ units)(λmax (H₂O)=261 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 6787.68; measured value: 6786.90).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2578-2596 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 8 Synthesis ofHO-A^(ms)-G^(e2s)-C^(e2s)-T^(e2s)-G^(e2s)-A^(ms)-T^(e2s)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(e2s)-C^(e2s)-A^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-CH₂CH₂OH(AO50)(SEQ ID NO: 200)

The compound of Example 5 having a sequence of interest was synthesizedin the same manner as in Example 1 except for using a program for 1 μmolscale [installed in the automated nucleic acid synthesizer (PerkinElmerABI model 394 DNA/RNA synthesizer)]. However, the portion with aphosphorothioate bond was sulfurized by treating with a mixed solutionof 0.02 M xanthane hydride/acetonitrile-pyridine (9:1 v/v mixture) for15 min, instead of the oxidation step with iodine-H₂O. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→55% (10 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at10.57 min was collected. When analyzed by ion exchange HPLC [column:Tosoh TSK-gel DEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile;solution B: 20% acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 MKBr, gradient: solution B 20→80% (10 min, linear gradient); 40° C.; 2ml/min], the subject compound was eluted at 7.38 min. (49.06 A₂₆₀ units)(λmax (H₂O)=261 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 6928.74; measured value: 6928.73).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2578-2596 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 9 Synthesis ofHO-A^(ms)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(ms)-T^(e2p)-C^(ms)-U^(ms)-G^(ms)-C^(ms)-U^(ms)-G^(ms)-G^(e2p)-C^(e2p)-A^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH(AO51)(SEQ ID NO: 200)

The compound of Example 5 having a sequence of interest was synthesizedin the same manner as in Example 8 using a program for 1 μmol scale.After deprotection, the resultant product was purified by reversed phaseHPLC [Shimadzu model LC-10VP; column: Merck, Chromolith PerformanceRP-18e (4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueoustriethylamine acetate (TEAA), pH 7.0; solution B: acetonitrile B %:10%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm]. Thefraction eluted at 5.20 min was collected. When analyzed by ion exchangeHPLC [column: Tosoh TSK-gel DEAE-5PW (7.5×75 mm); solution A: 20%acetonitrile; solution B: 20% acetonitrile, 67 mM phosphate buffer (pH6.8), 1.5 M KBr, gradient: solution B 20→80% (10 min, linear gradient);40° C.; 2 ml/min], the subject compound was eluted at 4.48 min. (30.78A₂₆₀ units) (λmax (H₂O)=260 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 6768.08; measured value: 6768.06).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2578-2596 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 10 Synthesis ofHO-A^(mp)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-G^(mp)-C^(e2p)-A^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH(AO52)(SEQ ID NO: 4)

The compound of Example 5 having a sequence of interest was synthesizedin the same manner as in Example 1. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→60% (10 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 5.32 min was collected. Whenanalyzed by reversed phase HPLC [column: Merck, Chromolith PerformanceRP-18e (4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueoustriethylamine acetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1M TEAA B %: 25%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254nm], the subject compound was eluted at 8.51 min. (1.67 A₂₆₀ units)(λmax (H₂O)=261 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 6691.60; measured value: 6691.37).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2578-2596 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 11 Synthesis ofHO-A^(ms)-G^(ms)-C^(e2s)-T^(e2s)-G^(ms)-A^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-G^(ms)-G^(ms)-C^(e2s)-A^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-CH₂CH₂OH(AO53)(SEQ ID NO: 4)

The compound of Example 5 having a sequence of interest was synthesizedin the same manner as in Example 8 using a program for 1 μmol scale.After deprotection, the resultant product was purified by reversed phaseHPLC [Shimadzu model LC-10VP; column: Merck, Chromolith PerformanceRP-18e (4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueoustriethylamine acetate (TEAA), pH 7.0; solution B: acetonitrile B %:10%→50% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm]. Thefraction eluted at 10.59 min was collected. When analyzed by ionexchange HPLC [column: Tosoh TSK-gel DEAE-5PW (7.5×75 mm); solution A:20% acetonitrile; solution B: 20% acetonitrile, 67 mM phosphate buffer(pH 6.8), 1.5 M KBr, gradient: solution B 20→80% (10 min, lineargradient); 40° C.; 2 ml/min], the subject compound was eluted at 6.61min. (36.63 A₂₆₀ units) (λmax (H₂O)=263 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 6996.86; measured value: 6996.80).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2578-2596 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 12 Synthesis ofHO-A^(ms)-G^(ms)-C^(e2p)-T^(e2p)-G^(ms)-A^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-G^(ms)-C^(e2p)-T^(e2p)-G^(ms)-G^(ms)-C^(e2p)-A^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH(AO54)(SEQ ID NO: 4)

The compound of Example 5 having a sequence of interest was synthesizedin the same manner as in Example 8 using a program for 1 μmol scale.After deprotection, the resultant product was purified by reversed phaseHPLC [Shimadzu model LC-10VP; column: Merck, Chromolith PerformanceRP-18e (4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueoustriethylamine acetate (TEAA), pH 7.0; solution B: acetonitrile B %:10%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm]. Thefraction eluted at 5.02 min was collected. When analyzed by ion exchangeHPLC [column: Tosoh TSK-gel DEAE-5PW (7.5×75 mm); solution A: 20%acetonitrile; solution B: 20% acetonitrile, 67 mM phosphate buffer (pH6.8), 1.5 M KBr, gradient: solution B 20→80% (10 min, linear gradient);40° C.; 2 ml/min], the subject compound was eluted at 4.51 min. (44.20A₂₆₀ units) (λmax (H₂O)=260 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 6820.13; measured value: 6820.12).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2578-2596 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 13 Synthesis ofHO-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(e2p)-T^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-CH₂CH₂OH(AO17)(SEQ ID NO: 202)

The compound of Example 13 having a sequence of interest was synthesizedin the same manner as in Example 1. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→45% (10 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 8.32 min was collected. Whenanalyzed by reversed phase HPLC [column: Merck, Chromolith PerformanceRP-18e (4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueoustriethylamine acetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1M TEAA B %: 15%→65% (10 min, linear gradient); 60° C.; 2 ml/min; 254nm], the subject compound was eluted at 7.14 min. (5.91 A₂₆₀ units)(λmax (H₂O)=260 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 6280.24; measured value: 6279.98).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2575-2592 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 14 Synthesis ofHO-G^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-U^(e2p)-G^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH(AO24)(SEQ ID NO: 197)

The compound of Example 14 having a sequence of interest was synthesizedin the same manner as in Example 1. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→55% (10 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 7.80 min was collected. Whenanalyzed by reversed phase HPLC [column: Merck, Chromolith PerformanceRP-18e (4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueoustriethylamine acetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1M TEAA B %: 15%→65% (10 min, linear gradient); 60° C.; 2 ml/min; 254nm], the subject compound was eluted at 8.89 min. (11.30 A₂₆₀ units)(λmax (H₂O)=261 nm)

The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 5369.71; measured value: 5369.20).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 2578-2592 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 15 Synthesis ofHO-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(e2p)-A^(mp)-G^(mp)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-C^(mp)-G^(mp)-A^(mp)-A^(mp)-A^(mp)-C^(mp)-U^(mp)-G^(e2p)-A^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-CH₂CH₂OH(AO20) (SEQ ID NO: 203)

The subject compound was synthesized with an automated nucleic acidsynthesizer (PerkinElmer ABI model 394 DNA/RNA synthesizer) using a 40nmol DNA program. The concentrations of solvents, reagents andphosphoroamidites at individual synthesis cycles were the same as usedin the synthesis of natural oligonucleotides. The solvents, reagents andphosphoroamidites of 2′-O-methylnucleoside (adenosine form: product No.27-1822-41; guanosine form: product No. 27-1826-41; citydine form:product No. 27-1823-02; uridine form: product No. 27-1825-42) wereproducts from Amersham Pharmacia. As non-natural phosphoroamidites,those compounds disclosed in Example 28(5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-6-N-benzoyladenosine-3′-O-(2-cyanoethylN,N-diisopropyl)phosphoroamidite), Example 41(5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-N-isobutylylguanosine-3′-O-(2-cyanoethylN,N-diisopropyl)phosphoroamidite), Example 36(5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-4-N-benzoyl-5-methylcitydine-3′-O-(2-cyanoethylN,N-diisopropyl)phosphoroamidite), and Example 23(5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-5-methyluridine-3′-O-(2-cyanoethylN,N-diisopropyl)phosphoroamidite) of Japanese Unexamined PatentPublication No. 2000-297097 were used. The subject compound wassynthesized using approx. 0.25 μmol of a modified control pore glass(CPG) (disclosed in Example 12b of Japanese Unexamined PatentPublication No. H7-87982) as a solid support. However, the time periodfor condensation of amidites was 15 min.

The protected oligonucleotide analogue having the sequence of interestwas treated with concentrated aqueous ammonia to thereby cut out theoligomer from the support and, at the same time, remove the protectivecyanoethyl groups on phosphorus atoms and the protective groups onnucleic acid bases. The solvent was distilled off under reducedpressure, and the resultant residue was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→55% (10 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.29min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (0.473 A₂₆₀ units) (λmax (H₂O)=259 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:10%→65% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 7.62 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value:7980.34).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6133-6155 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 16 Synthesis ofHO-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-C^(mp)-U^(mp)-U^(mp)-C^(mp)-G^(mp)-A^(mp)-A^(mp)-A^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-CH₂CH₂OH(AO26) (SEQ ID NO: 204)

The compound of Example 16 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→60% (10 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 9.76min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (7.93 A₂₆₀ units) (λmax (H₂O)=259 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→70% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 7.03 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 8094.48;measured value: 8093.74).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6133-6155 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 17 Synthesis ofHO-A^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-G^(mp)-C^(mp)-A^(mp)-A^(mp)-A^(mp)-U^(mp)-T^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH(AO55) (SEQ ID NO: 205)

The compound of Example 17 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→38% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 9.00min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (9.50 A₂₆₀ units) (λmax (H₂O)=259 nm). When analyzed by ionexchange HPLC [column: Tosoh TSK-gel DEAE-5PW (7.5×75 mm); solution A:20% acetonitrile; solution B: 20% acetonitrile, 67 mM phosphate buffer(pH 6.8), 1.5 M KBr; gradient: solution B 10→40% (10 min, lineargradient); 60° C.; 2 ml/min], the subject compound was eluted at 6.14min. The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 6350.31; measured value: 6350.07).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6125-6142 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 18 Synthesis ofHO-T^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-C^(mp)-A^(mp)-A^(mp)-A^(mp)-A^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-CH₂CH₂OH(AO56) (SEQ ID NO: 206)

The compound of Example 18 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→38% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.44min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (11.15 A₂₆₀ units) (λmax (H₂O)=260 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 6.38 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6254.21;measured value: 6254.15).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6136-6153 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 19 Synthesis ofHO-G^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-A^(mp)-A^(mp)-G^(mp)-U^(mp)-U^(mp)-G^(mp)-A^(mp)-G^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-CH₂CH₂OH(AO57) (SEQ ID NO: 207)

The compound of Example 19 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→38% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 8.06min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (9.60 A₂₆₀ units) (λmax (H₂O)=258 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.73 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6328.29;measured value: 6327.91).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6144-6161 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 20 Synthesis ofHO-T^(e2p)-T^(e2p)-G^(mp)-A^(mp)-G^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-A^(mp)-A^(mp)-A^(mp)-A^(mp)-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-CH₂CH₂OH(AO76) (SEQ ID NO: 12)

The compound of Example 20 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.30min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (13.64 A₂₆₀ units) (λmax (H₂O)=261 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 8.67 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6312.34;measured value: 6312.06).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6136-6153 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 21 Synthesis ofHO-T^(e2p)-T^(e2p)-G^(ms)-A^(ms)-G^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-A^(ms)-A^(ms)-A^(ms)-A^(ms)-C^(e2p)-T^(e2p)-G^(ms)-A^(ms)-CH₂CH₂OH(AO77) (SEQ ID NO: 12)

The compound of Example 21 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 v/v mixture) for 15 min, instead ofthe oxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→46% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.81 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (5.26 A₂₆₀units) (λmax (H₂O)=262 nm). When analyzed by reversed phase HPLC[column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: 25% acetonitrile, 0.1 M TEAA B %: 20%→80% (10 min, lineargradient); 60° C.; 2 ml/min; 254 nm], the subject compound was eluted at10.0 min. The compound was identified by negative ion ESI massspectrometric analysis (calculated value: 6456.94; measured value:6456.59).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6136-6153 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 22 Synthesis ofHO-T^(e2s)-T^(e2s)-G^(ms)-A^(ms)-G^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-T^(e2s)-C^(e2s)-A^(ms)-A^(ms)-A^(ms)-A^(ms)-C^(e2s)-T^(e2s)-G^(ms)-A^(ms)-CH₂CH₂OH(AO78) (SEQ ID NO: 12)

The compound of Example 22 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 v/v mixture) for 15 min, instead ofthe oxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→46% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.75 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (15.04 A₂₆₀units) (λmax (H₂O)=261 nm). When analyzed by reversed phase HPLC[column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: 25% acetonitrile, 0.1 M TEAA B %: 20%→80% (10 min, lineargradient); 60° C.; 2 ml/min; 254 nm], the subject compound was eluted at10.2 min. The compound was identified by negative ion ESI massspectrometric analysis (calculated value: 6601.53; measured value:6601.11).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6136-6153 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 23 Synthesis ofHO-G^(mp)-T^(e2p)-G^(mp)-C^(e2p)-A^(mp)-A^(mp)-A^(mp)-G^(mp)-T^(e2p)-T^(e2p)-G^(mp)-A^(mp)-G^(mp)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-CH₂CH₂OH(AO79) (SEQ ID NO: 13)

The compound of Example 23 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 5.95min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (11.73 A₂₆₀ units) (λmax (H₂O)=261 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 6.52 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6344.33;measured value: 6344.28).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6144-6161 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 24 Synthesis ofHO-G^(ms)-T^(e2p)-G^(ms)-C^(e2p)-A^(ms)-A^(ms)-A^(ms)-G^(ms)-T^(e2p)-T^(e2p)-G^(ms)-A^(ms)-G^(ms)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-CH₂CH₂OH(AO80) (SEQ ID NO: 13)

The compound of Example 24 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 v/v mixture) for 15 min, instead ofthe oxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→46% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.55 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (15.27 A₂₆₀units) (λmax (H₂O)=260 nm). When analyzed by reversed phase HPLC[column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: 25% acetonitrile, 0.1 M TEAA B %: 20%→80% (10 min, lineargradient); 60° C.; 2 ml/min; 254 nm], the subject compound was eluted at8.71 min. The compound was identified by negative ion ESI massspectrometric analysis (calculated value: 6488.93; measured value:6489.03).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6144-6161 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 25 Synthesis ofHO-G^(ms)-T^(e2s)-G^(ms)-C^(e2s)-A^(ms)-A^(ms)-A^(ms)-G^(ms)-T^(e2s)-T^(e2s)-G^(ms)-A^(ms)-G^(ms)-T^(e2s)-C^(e2s)-T^(e2s)-T^(e2s)-C^(e2s)-CH₂CH₂OH(AO81) (SEQ ID NO: 13)

The compound of Example 25 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 mixture) for 15 min, instead of theoxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→46% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.10 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (17.01 A₂₆₀units) (λmax (H₂O)=260 nm). When analyzed by reversed phase HPLC[column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: 25% acetonitrile, 0.1 M TEAA B %: 20%→80% (10 min, lineargradient); 60° C.; 2 ml/min; 254 nm], the subject compound was eluted at9.12 min. The compound was identified by negative ion ESI massspectrometric analysis (calculated value: 6633.53; measured value:6633.51).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6144-6161 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 26 Synthesis ofHO-G^(e2p)-C^(e2p)-C^(e2p)-G^(e2p)-C^(e2p)-U^(mp)-G^(mp)-C^(mp)-C^(mp)-C^(mp)-A^(e2p)-A^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-CH₂CH₂OH(AO33) (SEQ ID NO: 208)

The compound of Example 26 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (10 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.36min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (12.70 A₂₆₀ units) (λmax (H₂O)=261 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:15%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 7.92 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 5250.59;measured value: 5250.61).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6696-6710 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 27 Synthesis ofHo-C^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-C^(e2p)-C^(e2p)-A^(mp)-A^(mp)-T^(e2p)-G^(mp)-C^(e2p)-C^(e2p)-A^(mp)-U^(mp)-C^(e2p)-C^(e2p)-CH₂CH₂OH(AO85) (SEQ ID NO: 209)

The compound of Example 27 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 5.32min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (7.93 A₂₆₀ units) (λmax (H₂O)=261 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.63 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6263.34;measured value: 6263.40).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6691-6708 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 28 Synthesis ofHO-C^(e2p)-A^(mp)-G^(mp)-T^(e2p)-T^(e2p)-U^(mp)-G^(mp)-C^(e2p)-C^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-C^(e2p)-C^(e2p)-C^(e2p)-A^(mp)-A^(mp)-CH₂CH₂OH(AO86) (SEQ ID NO: 210)

The compound of Example 28 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.10min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (9.01 A₂₆₀ units) (λmax (H₂O)=260 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (8 min, linear gradient); 60° C.; 2 ml/min; 254 nm], the subjectcompound was eluted at 6.27 min. The compound was identified by negativeion ESI mass spectrometric analysis (calculated value: 6304.35; measuredvalue: 6304.47).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6699-6716 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 29 Synthesis ofHO-T^(e2p)-G^(mp)-T^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-C^(e2p)-A^(mp)-A^(mp)-C^(e2p)-A^(mp)-G^(mp)-T^(e2p)-T^(e2p)-T^(e2p)-G^(mp)-CH₂CH₂OH(AO87) (SEQ ID NO: 17)

The compound of Example 29 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 5.63min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (8.65 A₂₆₀ units) (λmax (H₂O)=259 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 6.06 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6331.33;measured value: 6331.14).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6710-6727 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 30 Synthesis ofHO-C^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-G^(ms)-C^(ms)-C^(e2s)-C^(e2s)-A^(ms)-A^(ms)-T^(e2s)-G^(ms)-C^(e2s)-C^(e2s)-A^(ms)-U^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OH(AO88) (SEQ ID NO: 209)

The compound of Example 30 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 mixture) for 15 min, instead of theoxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→46% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.57 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (12.02 A₂₆₀units) (λmax (H₂O)=262 nm). When analyzed by ion exchange [column: TosohTSK-gel DEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile; solution B:20% acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 M KBr; gradient:solution B 20→60% (10 min, linear gradient); 40° C.; 2 ml/min], thesubject compound was eluted at 7.11 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6552.54;measured value: 6553.12).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6691-6708 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 31 Synthesis ofHO-G^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-T^(e2p)-U^(mp)-C^(mp)-U^(mp)-U^(mp)-U^(mp)-U^(mp)-A^(mp)-G^(mp)-U^(mp)-U^(mp)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-CH₂CH₂OH(AO2) (SEQ ID NO: 211)

The compound of Example 31 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (10 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.13min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (3.91 A₂₆₀ units) (λmax (H₂O)=261 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:10%→50% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 9.95 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6859.54;measured value: 6858.95).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6973-6992 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 32 Synthesis ofHO-C^(mp)-U^(mp)-U^(mp)-U^(mp)-U^(mp)-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-U^(mp)-U^(mp)-U^(mp)-C^(mp)-C^(mp)-CH₂CH₂OH(AO23) (SEQ ID NO: 212)

The compound of Example 32 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.60min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (3.56 A₂₆₀ units) (λmax (H₂O)=261 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:15%→65% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 9.31 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 7496.97;measured value: 7496.53).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6965-6986 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 33 Synthesis ofHO-C^(e2p)-T^(e2p)-G^(e2p)-C^(e2p)-T^(e2p)-U^(mp)-C^(mp)-C^(mp)-U^(mp)-C^(mp)-C^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH(AO27) (SEQ ID NO: 214)

The compound of Example 33 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→55% (10 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.76min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (6.29 A₂₆₀ units) (λmax (H₂O)=265 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:15%→65% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 6.27 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 5160.54;measured value: 5159.90).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6921-6935 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 34 Synthesis ofHO-G^(e2p)-T^(e2p)-T^(e2p)-A^(e2p)-T^(e2p)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-U^(mp)-C^(mp)-C^(mp)-U^(mp)-C^(mp)-C^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH(AO28) (SEQ ID NO: 215)

The compound of Example 34 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.04min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (5.83 A₂₆₀ units) (λmax (H₂O)=263 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:15%→65% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 7.16 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6808.57;measured value: 6809.21).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6921-6940 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 35 Synthesis ofHO-C^(e2p)-T^(e2p)-T^(e2p)-T^(e2p)-T^(e2p)-A^(mp)-G^(mp)-U^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-G^(mp)-C^(mp)-U^(mp)-C^(mp)-U^(mp)-T^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH(AO29) (SEQ ID NO: 216)

The compound of Example 35 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.34min was collected. (1.83 A₂₆₀ units) (λmax (H₂O)=261 nm)

After the solvent was distilled off under reduced pressure, 80% aqueousacetic acid solution was added to the residue, which was then left for20 min to remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest. When analyzedby reversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:15%→65% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 7.45 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 7501.00;measured value: 7500.93).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6965-6986 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 36 Synthesis ofHO-T^(e2p)-T^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-C^(mp)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-U^(mp)-C^(mp)-A^(mp)-A^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-G^(e2p)-CH₂CH₂OH(AO48) (SEQ ID NO: 213)

The compound of Example 36 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (10 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.55min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (19.88 A₂₆₀ units) (λmax (H₂O)=259 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 8.72 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6291.22;measured value: 6290.99).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6953-6970 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 37 Synthesis ofHO-C^(e2s)-T^(e2s)-G^(e2s)-C^(e2s)-T^(e2s)-U^(ms)-C^(ms)-C^(ms)-U^(ms)-C^(ms)-C^(e2s)-A^(e2s)-A^(e2s)-C^(e2s)-C^(e2s)-CH₂CH₂OH(AO89) (SEQ ID NO: 214)

The compound of Example 37 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 v/v mixture) for 15 min, instead ofthe oxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→46% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 7.56 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (5.42 A₂₆₀units) (λmax (H₂O)=267 nm). When analyzed by ion exchange HPLC [column:Tosoh TSK-gel DEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile;solution B: 20% acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 MKBr, gradient: solution B 20→60% (10 min, linear gradient); 40° C.; 2ml/min], the subject compound was eluted at 6.10 min. The compound wasidentified by negative ion ESI mass spectrometric analysis (calculatedvalue: 5401.54; measured value: 5401.12).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6921-6935 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 38 Synthesis ofHO-C^(e2p)-U^(mp)-G^(mp)-C^(e2p)-U^(mp)-U^(mp)-C^(e2p)-C^(e2p)-U^(mp)-C^(e2p)-C^(e2p)-A^(mp)-A^(mp)-C^(e2p)-C^(e2p)-CH₂CH₂OH(AO90) (SEQ ID NO: 23)

The compound of Example 38 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→38% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.05min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (11.86 A₂₆₀ units) (λmax (H₂O)=266 nm). When analyzed by ionexchange HPLC [column: Tosoh TSK-gel DEAE-5PW (7.5×75 mm); solution A:20% acetonitrile; solution B: 20% acetonitrile, 67 mM phosphate buffer(pH 6.8), 1.5 M KBr, gradient: solution B 5→25% (10 min, lineargradient); 40° C.; 2 ml/min], the subject compound was eluted at 8.50min. The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 5150.55; measured value: 5150.69).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6921-6935 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 39 Synthesis ofHO-C^(e2s)-U^(ms)-G^(ms)-C^(e2s)-U^(ms)-U^(ms)-C^(e2s)-C^(e2s)-U^(ms)-C^(e2s)-C^(e2s)-A^(ms)-A^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OH(AO91) (SEQ ID NO: 23)

The compound of Example 39 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 v/v mixture) for 15 min, instead ofthe oxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→46% (10 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 7.21 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (10.77 A₂₆₀units) (λmax (H₂O)=266 nm). When analyzed by ion exchange HPLC [column:Tosoh TSK-gel DEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile;solution B: 20% acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 MKBr, gradient: solution B 20→60% (10 min, linear gradient); 40° C.; 2ml/min], the subject compound was eluted at 6.12 min. The compound wasidentified by negative ion ESI mass spectrometric analysis (calculatedvalue: 5391.55; measured value: 5391.76).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6921-6935 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 40 Synthesis ofHO-C^(e2p)-T^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-U^(mp)-C^(mp)-C^(e2p)-U^(mp)-C^(mp)-C^(e2p)-A^(mp)-A^(mp)-C^(e2p)-C^(e2p)-CH₂CH₂OH(AO92) (SEQ ID NO: 214)

The compound of Example 40 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→38% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.48min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (10.64 A₂₆₀ units) (λmax (H₂O)=266 nm). When analyzed by ionexchange HPLC [column: Tosoh TSK-gel DEAE-5PW (7.5×75 mm); solution A:20% acetonitrile; solution B: 20% acetonitrile, 67 mM phosphate buffer(pH 6.8), 1.5 M KBr, gradient: solution B 5→25% (10 min, lineargradient); 40° C.; 2 ml/min], the subject compound was eluted at 5.71min. The compound was identified by negative ion ESI mass spectrometricanalysis (calculated value: 5150.55; measured value: 5150.62).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6921-6935 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 41 Synthesis ofHO-C^(e2s)-T^(e2s)-G^(ms)-C^(e2s)-T^(e2s)-U^(ms)-C^(ms)-C^(e2s)-U^(ms)-C^(ms)-C^(e2s)-A^(ms)-A^(ms)-C^(e2s)-C^(e2s)-CH₂CH₂OH(AO93) (SEQ ID NO: 214)

The compound of Example 41 having a sequence of interest was synthesizedin the same manner as the compound of Example 15 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 v/v mixture) for 15 min, instead ofthe oxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→46% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 7.22 min was collected. (12.77A₂₆₀ units) (λmax (H₂O)=267 nm)

After the solvent was distilled off under reduced pressure, 80% aqueousacetic acid solution was added to the residue, which was then left for20 min to remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest. When analyzedby ion exchange HPLC [column: Tosoh TSK-gel DEAE-5PW (7.5×75 mm);solution A: 20% acetonitrile; solution B: 20% acetonitrile, 67 mMphosphate buffer (pH 6.8), 1.5 M KBr, gradient: solution B 20→60% (10min, linear gradient); 40° C.; 2 ml/min], the subject compound waseluted at 6.42 min. The compound was identified by negative ion ESI massspectrometric analysis (calculated value: 5391.55; measured value:5391.64).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6921-6935 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Reference Example 1 Synthesis of hAON4

hAON4 [FAM-CUG CUU CCU CCA ACC (SEQ ID NO: 23); all the nucleotides are2′-O-methylnucleotide and linked with each other by a phosphorothioatebond] which is disclosed in a document (van Deutekom, J. C. T. et al.(2001) Hum. Mol. Genet. 10, 1547-1554) and known as an oligonucleotidethat induces exon 46 skipping was synthesized according to the abovedocument.

FAM is a fluorescence group with the following structure.

Reference Example 2 Synthesis of hAON6

hAON6 [FAM-GUU AUC UGC UUC CUC CAA CC (SEQ ID NO: 24); all thenucleotides are 2′-O-methylnucleotide and linked with each other by aphosphorothioate bond] which is disclosed in a document (van Deutekom,J. C. T. et al. (2001) Hum. Mol. Genet. 10, 1547-1554) and known as anoligonucleotide that induces exon 46 skipping was synthesized accordingto the above document.

Reference Example 3

hAON8 [FAM-GCU UUU CUU UUA GUU GCU GC (SEQ ID NO: 25); all thenucleotides are 2′-O-methylnucleotide and linked with each other by aphosphorothioate bond] which is disclosed in a document (van Deutekom,J. C. T. et al. (2001) Hum. Mol. Genet. 10, 1547-1554) and known as anoligonucleotide that induces exon 46 skipping was synthesized accordingto the above document.

Example 42 Synthesis ofHO-G^(mp)-A^(e2p)-A^(mp)-A^(mp)-A^(mp)-C^(e2p)-G^(mp)-C^(e2p)-C^(e2p)-G^(mp)-C^(mp)-C^(e2p)-A^(mp)-T^(e2p)-U^(mp)-U^(mp)-C^(e2p)-T^(e2p)-CH₂CH₂OH(AO100)(SEQ ID NO: 30)

The subject compound was synthesized with an automated nucleic acidsynthesizer (PerkinElmer ABI model 394 DNA/RNA synthesizer) at a 40 nmolscale. The concentrations of solvents, reagents and phosphoroamidites atindividual synthesis cycles were the same as used in the synthesis ofnatural oligonucleotides. The solvents, reagents and phosphoroamiditesof 2′-O-methylnucleoside (adenosine form: product No. 27-1822-41;guanosine form: product No. 27-1826-41; citydine form: product No.27-1823-02; uridine form: product No. 27-1825-42) were products fromAmersham Pharmacia. As non-natural phosphoroamidites, those compoundsdisclosed in Example 55(5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-6-N-benzoyladenosine-3′-O-(2-cyanoethylN,N-diisopropyl)phosphoroamidite), Example 68(5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-N-isobutylylguanosine-3′-O-(2-cyanoethylN,N-diisopropyl)phosphoroamidite), Example 63(5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-4-N-benzoyl-5-methylcitydine-3′-O-(2-cyanoethylN,N-diisopropyl)phosphoroamidite), and Example 50(5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-5-methyluridine-3′-O-(2-cyanoethylN,N-diisopropyl)phosphoroamidite) of Japanese Unexamined PatentPublication No. 2000-297097 were used. The subject compound wassynthesized on a modified control pore glass (CPG) (disclosed in Example12b of Japanese Unexamined Patent Publication No. H7-87982) as a solidsupport. However, the time period for condensation of amidites was 15min.

The protected oligonucleotide analogue having the sequence of interestwas treated with concentrated aqueous ammonia to thereby cut out theoligomer from the support and, at the same time, remove the protectivecyanoethyl groups on phosphorus atoms and the protective groups onnucleic acid bases. The solvent was distilled off under reducedpressure, and the resultant residue was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.55min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (1.40 A₂₆₀ units) (λmax (H₂O)=264 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.40 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6246.28;measured value: 6245.68).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6555-6572 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 43 Synthesis ofHO-C^(e2p)-T^(e2p)-G^(mp)-U^(mp)-T^(e2p)-A^(mp)-G^(mp)-C^(e2p)-C^(mp)-A^(mp)-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-T^(e2p)-T^(e2p)-A^(mp)-A^(mp)-CH₂CH₂OH(AO102)(SEQ ID NO: 31)

The compound of Example 43 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.76min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (14.2 A₂₆₀ units) (λmax (H₂O)=260 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:15%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 6.42 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6262.27;measured value: 6261.87).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6591-6608 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 44 Synthesis ofHO-T^(e2p)-G^(mp)-A^(mp)-G^(mp)-A^(e2p)-A^(mp)-A^(mp)-C^(e2p)-T^(e2p)-G^(mp)-T^(e2p)-U^(mp)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-U^(mp)-T^(e2p)-CH₂CH₂OH(AO103)(SEQ ID NO: 32)

The compound of Example 44 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 8.12min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (0.204 A₂₆₀ units) (λmax (H₂O)=260 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.84 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6288.27;measured value: 6288.16).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6609-6626 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 45 Synthesis ofHO-C^(e2p)-A^(mp)-G^(mp)-G^(mp)-A^(e2p)-A^(mp)-T^(e2p)-T^(e2p)-U^(mp)-G^(mp)-T^(e2p)-G^(mp)-U^(mp)-C^(e2p)-U^(mp)-U^(mp)-T^(e2p)-C^(e2p)-CH₂CH₂OH(AO104)(SEQ ID NO: 33)

The compound of Example 45 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.46min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (3.73 A₂₆₀ units) (λmax (H₂O)=261 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 6.20 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6242.19;measured value: 6241.47).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6627-6644 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 45 Synthesis ofHO-G^(mp)-T^(e2p)-A^(mp)-U^(mp)-T^(e2p)-T^(e2p)-A^(mp)-G^(mp)-C^(e2p)-A^(mp)-T^(e2p)-G^(mp)-U^(mp)-T^(e2p)-C^(mp)-C^(e2p)-C^(e2p)-A^(mp)-CH₂CH₂OH(AO105)(SEQ ID NO: 34)

The compound of Example 46 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.11min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (14.8 A₂₆₀ units) (λmax (H₂O)=260 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:15%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 6.04 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6239.23;measured value: 6238.90).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6650-6667 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 47 Synthesis ofHO-A^(mp)-G^(mp)-C^(e2p)-A^(mp)-T^(e2p)-G^(mp)-T^(e2p)-T^(e2p)-C^(mp)-C^(mp)-C^(e2p)-A^(mp)-A^(mp)-T^(e2p)-U^(mp)-C^(mp)-T^(e2p)-C^(e2p)-CH₂CH₂OH(AO106)(SEQ ID NO: 35)

The compound of Example 47 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.51min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (6.97 A₂₆₀ units) (λmax (H₂O)=261 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:15%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 6.22 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6198.22;measured value: 6197.87).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6644-6661 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 48 Synthesis ofHO-C^(mp)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-A^(mp)-T^(e2p)-C^(e2p)-U^(mp)-U^(mp)-C^(e2p)-T^(e2p)-A^(mp)-A^(mp)-C^(e2p)-U^(mp)-U^(mp)-C^(e2p)-CH₂CH₂OH(AO108)(SEQ ID NO: 40)

The compound of Example 48 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.74min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (4.91 A₂₆₀ units) (λmax (H₂O)=263 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.94 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6159.18;measured value: 6159.35).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7447-7464 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 49 Synthesis ofHO-A^(mp)-C^(e2p)-C^(e2p)-G^(mp)-C^(mp)-C^(e2p)-T^(e2p)-U^(mp)-C^(mp)-C^(e2p)-A^(mp)-C^(mp)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-A^(e2p)-G^(mp)-CH₂CH₂OH(AO109)(SEQ ID NO: 41)

The compound of Example 49 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.72min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (3.30 A₂₆₀ units) (λmax (H₂O)=261 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.53 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6221.27;measured value: 6220.43).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7465-7482 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 50 Synthesis ofHO-T^(e2p)-C^(mp)-T^(e2p)-T^(e2p)-G^(mp)-A^(mp)-A^(mp)-G^(mp)-T^(e2p)-A^(mp)-A^(e2p)-A^(mp)-C^(e2p)-G^(mp)-G^(mp)-T^(e2p)-U^(mp)-T^(e2p)-CH₂CH₂OH(AO110)(SEQ ID NO: 42)

The compound of Example 50 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (10 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.18min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (3.92 A₂₆₀ units) (λmax (H₂O)=258 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.66 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6289.26;measured value: 6288.99).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7483-7500 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 51 Synthesis ofHO-G^(mp)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-T^(e2p)-T^(e2p)-U^(mp)-G^(mp)-C^(e2p)-C^(mp)-C^(mp)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-CH₂CH₂OH(AO111)(SEQ ID NO: 43)

The compound of Example 51 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 5.91min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (9.48 A₂₆₀ units) (λmax (H₂O)=260 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 4.81 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6245.24;measured value: 6244.86).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7501-7518 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 52 Synthesis ofHO-A^(mp)-G^(mp)-T^(e2p)-C^(e2p)-C^(e2p)-A^(mp)-G^(mp)-G^(mp)-A^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-A^(mp)-G^(mp)-G^(mp)-T^(e2p)-C^(e2p)-A^(mp)-CH₂CH₂OH(AO112)(SEQ ID NO: 44)

The compound of Example 52 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.00min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (0.200 A₂₆₀ units) (λmax (H₂O)=253 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 4.33 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6365.37;measured value: 6365.99).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7519-7536 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 53 Synthesis ofHO-G^(mp)-C^(e2p)-T^(e2p)-C^(mp)-C^(e2p)-A^(mp)-A^(mp)-T^(e2p)-A^(mp)-G^(mp)-T^(e2p)-G^(mp)-G^(mp)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-T^(e2p)-CH₂CH₂OH(AO113)(SEQ ID NO: 45)

The compound of Example 53 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 5.22min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (4.96 A₂₆₀ units) (λmax (H₂O)=260 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 4.96 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6317.31;measured value: 6317.06).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7534-7551 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 54 Synthesis ofHO-G^(mp)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-C^(e2p)-U^(mp)-C^(mp)-T^(e2p)-C^(mp)-G^(mp)-C^(e2p)-T^(e2p)-C^(mp)-A^(mp)-C^(e2p)-T^(e2p)-C^(mp)-CH₂CH₂OH(AO114)(SEQ ID NO: 47)

The compound of Example 54 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 5.13min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (2.02 A₂₆₀ units) (λmax (H₂O)=267 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.89 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6188.23;measured value: 6187.79).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8275-8292 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 55 Synthesis ofHO-T^(e2p)-C^(e2p)-U^(mp)-U^(mp)-C^(e2p)-C^(e2p)-A^(mp)-A^(mp)-A^(mp)-G^(mp)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-C^(mp)-U^(mp)-C^(e2p)-T^(e2p)-CH₂CH₂OH(AO115)(SEQ ID NO: 48)

The compound of Example 55 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.08min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (2.68 A₂₆₀ units) (λmax (H₂O)=262 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.85 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6197.24;measured value: 6196.74).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8284-8301 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 56 Synthesis ofHO-T^(e2p)-G^(mp)-C^(e2p)-A^(mp)-G^(mp)-T^(e2p)-A^(mp)-A^(mp)-T^(e2p)-C^(e2p)-U^(mp)-A^(mp)-T^(e2p)-G^(mp)-A^(mp)-G^(mp)-T^(e2p)-T^(e2p)-CH₂CH₂OH(AO116)(SEQ ID NO: 49)

The compound of Example 56 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.02min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (13.40 A₂₆₀ units) (λmax (H₂O)=260 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 6.55 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6303.28;measured value: 6302.90).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8302-8319 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 57 Synthesis ofHO-G^(mp)-T^(e2p)-T^(e2p)-U^(mp)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-U^(mp)-T^(e2p)-C^(mp)-T^(e2p)-G^(mp)-T^(e2p)-A^(mp)-A^(mp)-G^(mp)-C^(e2p)-CH₂CH₂OH(AO118)(SEQ ID NO: 50)

The compound of Example 57 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.69min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (8.16 A₂₆₀ units) (λmax (H₂O)=261 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.69 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6255.23;measured value: 6254.64).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8356-8373 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 58 Synthesis ofHO-T^(e2p)-G^(mp)-T^(e2p)-A^(mp)-G^(mp)-G^(mp)-A^(mp)-C^(e2p)-A^(mp)-T^(e2p)-T^(e2p)-G^(mp)-G^(mp)-C^(e2p)-A^(mp)-G^(mp)-T^(e2p)-T^(e2p)-CH₂CH₂OH(AO119)(SEQ ID NO: 51)

The compound of Example 58 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.62min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (8.06 A₂₆₀ units) (λmax (H₂O)=259 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.72 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6358.32;measured value: 6357.91).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8374-8391 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 59 Synthesis ofHO-T^(e2p)-C^(mp)-C^(mp)-T^(e2p)-T^(e2p)-A^(mp)-C^(e2p)-G^(mp)-G^(mp)-G^(mp)-T^(e2p)-A^(mp)-G^(mp)-C^(e2p)-A^(mp)-U^(mp)-C^(e2p)-C^(e2p)-CH₂CH₂OH(AO120)(SEQ ID NO: 52)

The compound of Example 59 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.14min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (0.459 A₂₆₀ units) (λmax (H₂O)=260 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.09 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6253.26;measured value: 6253.06).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8392-8409 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 60 Synthesis ofHO-A^(mp)-G^(mp)-C^(e2p)-T^(e2p)-C^(mp)-U^(mp)-T^(e2p)-U^(mp)-T^(e2p)-A^(mp)-C^(mp)-T^(e2p)-C^(e2p)-C^(mp)-C^(mp)-T^(e2p)-T^(e2p)-G^(mp)-CH₂CH₂OH(AO122)(SEQ ID NO: 53)

The compound of Example 60 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.13min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (7.93 A₂₆₀ units) (λmax (H₂O)=263 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.55 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6152.14;measured value: 6151.48).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8428-8445 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 61 Synthesis ofHO-C^(e2p)-C^(e2p)-A^(mp)-U^(mp)-T^(e2p)-G^(mp)-U^(mp)-T^(e2p)-U^(mp)-C^(e2p)-A^(mp)-U^(mp)-C^(e2p)-A^(mp)-G^(mp)-C^(mp)-T^(e2p)-C^(e2p)-CH₂CH₂OH(AO123)(SEQ ID NO: 54)

The compound of Example 61 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.71min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (9.66 A₂₆₀ units) (λmax (H₂O)=263 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.69 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6175.18;measured value: 6174.65).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8441-8458 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 62 Synthesis ofHO-G^(mp)-C^(e2p)-C^(e2p)-G^(mp)-C^(e2p)-C^(mp)-A^(mp)-T^(e2p)-U^(mp)-U^(mp)-C^(e2p)-U^(mp)-C^(e2p)-A^(mp)-A^(mp)-C^(e2p)-A^(e2p)-G^(mp)-CH₂CH₂OH(AO124)(SEQ ID NO: 36)

The compound of Example 62 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.59min was collected. (12.70 A₂₆₀ units).

After the solvent was distilled off under reduced pressure, 80% aqueousacetic acid solution was added to the residue, which was then left for20 min to remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest. When analyzedby reversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (8 min, linear gradient); 60° C.; 2 ml/min; 254 nm], the subjectcompound was eluted at 6.13 min. The compound was identified by negativeion ESI mass spectrometric analysis (calculated value: 6222.25; measuredvalue: 6222.24).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6549-6566 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 63 Synthesis ofHO-C^(e2p)-A^(mp)-T^(e2p)-A^(mp)-A^(mp)-T^(e2p)-G^(mp)-A^(mp)-A^(e2p)-A^(mp)-A^(mp)-C^(e2p)-G^(mp)-C^(mp)-C^(e2p)-G^(mp)-C^(e2p)-C^(e2p)-CH₂CH₂OH(AO125)(SEQ ID NO: 37)

The compound of Example 63 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.68min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (11.74 A₂₆₀ units). When analyzed by reversed phase HPLC[column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: 25% acetonitrile, 0.1 M TEAA B %: 20%→80% (8 min, lineargradient); 60° C.; 2 ml/min; 254 nm], the subject compound was eluted at7.41 min. The compound was identified by negative ion ESI massspectrometric analysis (calculated value: 6292.36; measured value:6292.55).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6561-6578 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 64 Synthesis ofHO-T^(e2p)-U^(mp)-C^(e2p)-C^(mp)-C^(e2p)-A^(mp)-A^(mp)-T^(e2p)-U^(mp)-C^(mp)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-G^(mp)-A^(e2p)-A^(mp)-T^(e2p)-CH₂CH₂OH(AO126)(SEQ ID NO: 38)

The compound of Example 64 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.91min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (13.31 A₂₆₀ units). When analyzed by reversed phase HPLC[column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: 25% acetonitrile, 0.1 M TEAA B %: 20%→80% (8 min, lineargradient); 60° C.; 2 ml/min; 254 nm], the subject compound was eluted at6.25 min. The compound was identified by negative ion ESI massspectrometric analysis (calculated value: 6208.22; measured value:6208.15).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6638-6655 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 65 Synthesis ofHO-C^(e2p)-C^(e2p)-A^(mp)-U^(mp)-T^(e2p)-U^(mp)-G^(mp)-T^(e2p)-A^(mp)-U^(mp)-T^(e2p)-T^(e2p)-A^(mp)-G^(mp)-C^(e2p)-A^(mp)-T^(e2p)-G^(mp)-CH₂CH₂OH(AO127)(SEQ ID NO: 39)

The compound of Example 65 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.49min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (11.38 A₂₆₀ units). When analyzed by reversed phase HPLC[column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: 25% acetonitrile, 0.1 M TEAA B %: 20%→80% (8 min, lineargradient); 60° C.; 2 ml/min; 254 nm], the subject compound was eluted at6.24 min. The compound was identified by negative ion ESI massspectrometric analysis (calculated value: 6240.22; measured value:6239.82).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6656-6673 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 66 Synthesis ofHO-G^(mp)-C^(e2p)-T^(e2p)-A^(mp)-G^(mp)-G^(mp)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-G^(mp)-C^(e2p)-T^(e2p)-G^(mp)-C^(mp)-T^(e2p)-T^(e2p)-U^(mp)-CH₂CH₂OH(AO128)(SEQ ID NO: 46)

The compound of Example 66 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 5.61min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (1.11 A₂₆₀ units). When analyzed by reversed phase HPLC[column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: 25% acetonitrile, 0.1 M TEAA B %: 20%→80% (8 min, lineargradient); 60° C.; 2 ml/min; 254 nm], the subject compound was eluted at5.59 min. The compound was identified by negative ion ESI massspectrometric analysis (calculated value: 6310.27; measured value:6310.33).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7510-7527 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 67 Synthesis ofHO-C^(mp)-T^(e2p)-A^(mp)-T^(e2p)-G^(mp)-A^(mp)-G^(mp)-T^(e2p)-T^(e2p)-T^(e2p)-C^(mp)-T^(e2p)-T^(e2p)-C^(mp)-C^(mp)-A^(mp)-A^(e2p)-A^(mp)-CH₂CH₂OH(AO129)(SEQ ID NO: 55)

The compound of Example 67 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.83min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (2.21 A₂₆₀ units). When analyzed by reversed phase HPLC[column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: 25% acetonitrile, 0.1 M TEAA B %: 20%→80% (8 min, lineargradient); 60° C.; 2 ml/min; 254 nm], the subject compound was eluted at6.70 min. The compound was identified by negative ion ESI massspectrometric analysis (calculated value: 6209.21; measured value:6209.06).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8293-8310 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Exon 51 Example 68 Synthesis ofPh-T^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-T^(e2p)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(mp)-A^(e2p)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-CH₂CH₂OH(AO3)(SEQ ID NO: 56)

The compound of Example 68 having a sequence of interest was synthesizedin the same manner as in Example 42, except that phenyl 2-cyanoethylN,N-diisopropylphosphoramidite (Hotoda, H. et al. Nucleosides &Nucleotides 15, 531-538, (1996)) was used in the final condensation tointroduce phenylphosphate on the 5′ terminal side. After deprotection,the resultant product was purified by reversed phase HPLC [Shimadzumodel LC-10VP; column: Merck, Chromolith Performance RP-18e (4.6×100mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamine acetate(TEAA), pH 7.0; solution B: acetonitrile B %: 5%→15% (10 min, lineargradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 5.24 minwas collected. After distilling off the solvent, the resultant residuewas dissolved in 0.5 ml of water and filtered with Ultrafree-MC(Millipore: product No. UFC4 OHV 25). The solvent was distilled off tothereby obtain the compound of interest (1.21 A₂₆₀ units) (λmax(H₂O)=259 nm). When analyzed by reversed phase HPLC [column: Merck,Chromolith Performance RP-18e (4.6×100 mm); solution A: 5% acetonitrile,0.1 M aqueous triethylamine acetate (TEAA), pH 7.0; solution B:acetonitrile B %: 5%→15% (10 min, linear gradient); 60° C.; 2 ml/min;254 nm], the subject compound was eluted at 5.79 min. The compound wasidentified by negative ion ESI mass spectrometric analysis (calculatedvalue: 6240.22; measured value: 6239.82).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7565-7584 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 69 Synthesis ofPh-A^(e2p)-G^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-G^(mp)-U^(mp)-G^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(e2p)-G^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-CH₂CH₂OH(AO4)(SEQ ID NO: 57)

The compound of Example 69 having a sequence of interest was synthesizedin the same manner as in Example 42, except that phenyl 2-cyanoethylN,N-diisopropylphosphoramidite (Hotoda, H. et al. Nucleosides &Nucleotides 15, 531-538, (1996)) was used in the final condensation tointroduce phenylphosphate on the 5′ terminal side. After deprotection,the resultant product was purified by reversed phase HPLC [Shimadzumodel LC-10VP; column: Merck, Chromolith Performance RP-18e (4.6×100mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamine acetate(TEAA), pH 7.0; solution B: acetonitrile B %: 5%→15% (10 min, lineargradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.23 minwas collected. After distilling off the solvent, the resultant residuewas dissolved in 0.5 ml of water and filtered with Ultrafree-MC(Millipore: product No. UFC4 OHV 25). The solvent was distilled off tothereby obtain the compound of interest (2.67 A₂₆₀ units) (λmax(H₂O)=259 nm). When analyzed by reversed phase HPLC [column: Merck,Chromolith Performance RP-18e (4.6×100 mm); solution A: 5% acetonitrile,0.1 M aqueous triethylamine acetate (TEAA), pH 7.0; solution B:acetonitrile B %: 5%→15% (10 min, linear gradient); 60° C.; 2 ml/min;254 nm], the subject compound was eluted at 6.45 min. The compound wasidentified by negative ion ESI mass spectrometric analysis (calculatedvalue: 7153.77; measured value: 7152.95).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7569-7588 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 70 Synthesis ofPh-A^(e2p)-G^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-C^(mp)-C^(mp)-A^(mp)-C^(mp)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-U^(mp)-G^(mp)-T^(e2p)-G^(e2p)-T^(e2p)-C^(e2p)-A^(e2p)-CH₂CH₂OH(AO5)(SEQ ID NO: 58)

The compound of Example 70 having a sequence of interest was synthesizedin the same manner as in Example 42, except that phenyl 2-cyanoethylN,N-diisopropylphosphoramidite (Hotoda, H. et al. Nucleosides &Nucleotides 15, 531-538, (1996)) was used in the final condensation tointroduce phenylphosphate on the 5′ terminal side. After deprotection,the resultant product was purified by reversed phase HPLC [Shimadzumodel LC-10VP; column: Merck, Chromolith Performance RP-18e (4.6×100mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamine acetate(TEAA), pH 7.0; solution B: acetonitrile B %: 5%→15% (10 min, lineargradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 4.71 minwas collected. After distilling off the solvent, the resultant residuewas dissolved in 0.5 ml of water and filtered with Ultrafree-MC(Millipore: product No. UFC4 OHV 25). The solvent was distilled off tothereby obtain the compound of interest (0.836 A₂₆₀ units) (λmax(H₂O)=259 nm). When analyzed by reversed phase HPLC [column: Merck,Chromolith Performance RP-18e (4.6×100 mm); solution A: 5% acetonitrile,0.1 M aqueous triethylamine acetate (TEAA), pH 7.0; solution B:acetonitrile B %: 5%→15% (10 min, linear gradient); 60° C.; 2 ml/min;254 nm], the subject compound was eluted at 5.56 min. The compound wasidentified by negative ion ESI mass spectrometric analysis (calculatedvalue: 7127.78; measured value: 7127.27).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7578-7597 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 71 Synthesis ofPh-T^(e2p)-T^(e2p)-G^(e2p)-A^(e2p)-T^(e2p)-C^(mp)-A^(mp)-A^(mp)-G^(mp)-C^(mp)-A^(mp)-G^(mp)-A^(mp)-G^(mp)-A^(mp)-A^(e2p)-A^(e2p)-G^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH(AO6)(SEQ ID NO: 59)

The compound of Example 71 having a sequence of interest was synthesizedin the same manner as in Example 42, except that phenyl 2-cyanoethylN,N-diisopropylphosphoramidite (Hotoda, H. et al. Nucleosides &Nucleotides 15, 531-538, (1996)) was used in the final condensation tointroduce phenylphosphate on the 5′ terminal side. After deprotection,the resultant product was purified by reversed phase HPLC [Shimadzumodel LC-10VP; column: Merck, Chromolith Performance RP-18e (4.6×100mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamine acetate(TEAA), pH 7.0; solution B: acetonitrile B %: 5%→15% (10 min, lineargradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.79 minwas collected. After distilling off the solvent, the resultant residuewas dissolved in 0.5 ml of water and filtered with Ultrafree-MC(Millipore: product No. UFC4 OHV 25). The solvent was distilled off tothereby obtain the compound of interest (2.04 A₂₆₀ units) (λmax(H₂O)=258 nm). When analyzed by reversed phase HPLC [column: Merck,Chromolith Performance RP-18e (4.6×100 mm); solution A: 5% acetonitrile,0.1 M aqueous triethylamine acetate (TEAA), pH 7.0; solution B:acetonitrile B %: 5%→15% (10 min, linear gradient); 60° C.; 2 ml/min;254 nm], the subject compound was eluted at 7.81 min. The compound wasidentified by negative ion ESI mass spectrometric analysis (calculatedvalue: 7187.88; measured value: 7187.41).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7698-7717 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 72 Synthesis ofPh-C^(e2p)-A^(e2p)-C^(e2p)-C^(e2p)-C^(e2p)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-U^(mp)-G^(mp)-A^(mp)-U^(mp)-U^(mp)-U^(mp)-T^(e2p)-A^(e2p)-T^(e2p)-A^(e2p)-A^(e2p)-CH₂CH₂OH(AO8)(SEQ ID NO: 60)

The compound of Example 72 having a sequence of interest was synthesizedin the same manner as in Example 42, except that phenyl 2-cyanoethylN,N-diisopropylphosphoramidite (Hotoda, H. et al. Nucleosides &Nucleotides 15, 531-538, (1996)) was used in the final condensation tointroduce phenylphosphate on the 5′ terminal side. After deprotection,the resultant product was purified by reversed phase HPLC [Shimadzumodel LC-10VP; column: Merck, Chromolith Performance RP-18e (4.6×100mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamine acetate(TEAA), pH 7.0; solution B: acetonitrile B %: 5%→13% (8 min, lineargradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.20 minwas collected. After distilling off the solvent, the resultant residuewas dissolved in 0.5 ml of water and filtered with Ultrafree-MC(Millipore: product No. UFC4 OHV 25). The solvent was distilled off tothereby obtain the compound of interest (2.64 A₂₆₀ units) (λmax(H₂O)=260 nm). When analyzed by reversed phase HPLC [column: Merck,Chromolith Performance RP-18e (4.6×100 mm); solution A: 5% acetonitrile,0.1 M aqueous triethylamine acetate (TEAA), pH 7.0; solution B:acetonitrile B %: 5%→15% (10 min, linear gradient); 60° C.; 2 ml/min;254 nm], the subject compound was eluted at 7.07 min. The compound wasidentified by negative ion ESI mass spectrometric analysis (calculatedvalue: 7014.69; measured value: 7014.45).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7719-7738 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 73 Synthesis ofPh-A^(e2p)-C^(e2p)-C^(e2p)-C^(e2p)-A^(e2p)-C^(mp)-C^(mp)-A^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-C^(mp)-U^(mp)-C^(e2p)-T^(e2p)-G^(e2p)-T^(e2p)-G^(e2p)-CH₂CH₂OH(AO9)(SEQ ID NO: 61)

The compound of Example 73 having a sequence of interest was synthesizedin the same manner as in Example 42, except that phenyl 2-cyanoethylN,N-diisopropylphosphoramidite (Hotoda, H. et al. Nucleosides &Nucleotides 15, 531-538, (1996)) was used in the final condensation tointroduce phenylphosphate on the 5′ terminal side. After deprotection,the resultant product was purified by reversed phase HPLC [Shimadzumodel LC-10VP; column: Merck, Chromolith Performance RP-18e (4.6×100mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamine acetate(TEAA), pH 7.0; solution B: acetonitrile B %: 5%→15% (10 min, lineargradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.74 minwas collected. After distilling off the solvent, the resultant residuewas dissolved in 0.5 ml of water and filtered with Ultrafree-MC(Millipore: product No. UFC4 OHV 25). The solvent was distilled off tothereby obtain the compound of interest (3.08 A₂₆₀ units) (λmax(H₂O)=265 nm). When analyzed by reversed phase HPLC [column: Merck,Chromolith Performance RP-18e (4.6×100 mm); solution A: 5% acetonitrile,0.1 M aqueous triethylamine acetate (TEAA), pH 7.0; solution B:acetonitrile B %: 5%→15% (10 min, linear gradient); 60° C.; 2 ml/min;254 nm], the subject compound was eluted at 7.20 min. The compound wasidentified by negative ion ESI mass spectrometric analysis (calculatedvalue: 6986.72; measured value: 6986.81).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7728-7747 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 74 Synthesis ofPh-C^(e2p)-C^(e2p)-T^(e2p)-C^(e2p)-A^(e2p)-A^(mp)-G^(mp)-G^(mp)-U^(mp)-C^(mp)-A^(mp)-C^(mp)-C^(mp)-C^(mp)-A^(mp)-C^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-C^(e2p)-CH₂CH₂OH(AO10)(SEQ ID NO: 62)

The compound of Example 74 having a sequence of interest was synthesizedin the same manner as in Example 42, except that phenyl 2-cyanoethylN,N-diisopropylphosphoramidite (Hotoda, H. et al. Nucleosides &Nucleotides 15, 531-538, (1996)) was used in the final condensation tointroduce phenylphosphate on the 5′ terminal side. After deprotection,the resultant product was purified by reversed phase HPLC [Shimadzumodel LC-10VP; column: Merck, Chromolith Performance RP-18e (4.6×100mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamine acetate(TEAA), pH 7.0; solution B: acetonitrile B %: 5%→15% (10 min, lineargradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.62 minwas collected. After distilling off the solvent, the resultant residuewas dissolved in 0.5 ml of water and filtered with Ultrafree-MC(Millipore: product No. UFC4 OHV 25). The solvent was distilled off tothereby obtain the compound of interest (3.31 A₂₆₀ units) (λmax(H₂O)=266 nm). When analyzed by reversed phase HPLC [column: Merck,Chromolith Performance RP-18e (4.6×100 mm); solution A: 5% acetonitrile,0.1 M aqueous triethylamine acetate (TEAA), pH 7.0; solution B:acetonitrile B %: 5%→15% (10 min, linear gradient); 60° C.; 2 ml/min;254 nm], the subject compound was eluted at 6.46 min. The compound wasidentified by negative ion ESI mass spectrometric analysis (calculatedvalue: 7037.82; measured value: 7036.73).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7738-7757 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 75 Synthesis ofHO-T^(e2p)-A^(e2p)-A^(e2p)-C^(e2p)-A^(e2p)-G^(mp)-U^(mp)-C^(mp)-U^(mp)-G^(mp)-A^(mp)-G^(mp)-U^(mp)-A^(e2p)-G^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-CH₂CH₂OH(AO37)(SEQ ID NO: 63)

The compound of Example 75 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (10 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.64min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (17.9 A₂₆₀ units) (λmax (H₂O)=257 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 9.03 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6344.26;measured value: 6343.66).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7554-7571 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 76 Synthesis ofHO-G^(e2p)-G^(e2p)-C^(e2p)-A^(e2p)-T^(e2p)-U^(mp)-U^(mp)-C^(mp)-U^(mp)-A^(mp)-G^(mp)-U^(mp)-U^(mp)-T^(e2p)-G^(e2p)-G^(e2p)-A^(e2p)-G^(e2p)-CH₂CH₂OH(AO39)(SEQ ID NO: 64)

The compound of Example 76 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (10 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.82min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (17.5 A₂₆₀ units) (λmax (H₂O)=259 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 7.51 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6289.17;measured value: 6289.10).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7612-7629 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 77 Synthesis ofHO-A^(e2p)-G^(e2p)-C^(e2p)-C^(e2p)-A^(e2p)-G^(mp)-U^(mp)-C^(mp)-G^(mp)-G^(mp)-U^(mp)-A^(mp)-A^(mp)-G^(e2p)-T^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-CH₂CH₂OH(AO43)(SEQ ID NO: 65)

The compound of Example 77 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (10 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.76min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (6.57 A₂₆₀ units) (λmax (H₂O)=258 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 8.90 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6313.28;measured value: 6313.15).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7684-7701 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 78 Synthesis ofHO-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-T^(e2p)-G^(mp)-G^(mp)-A^(mp)-G^(mp)-A^(mp)-U^(mp)-G^(mp)-G^(mp)-C^(e2p)-A^(e2p)-G^(e2p)-T^(e2p)-T^(e2p)-CH₂CH₂OH(AO58)(SEQ ID NO: 66)

The compound of Example 78 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→38% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.62min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (10.7 A₂₆₀ units) (λmax (H₂O)=258 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 4.80 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6313.28;measured value: 6313.15).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7603-7620 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Exon 53 Example 79 Synthesis ofHO-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-T^(e2p)-T^(e2p)-C^(mp)-T^(e2p)-G^(mp)-A^(mp)-A^(mp)-T^(e2p)-T^(e2p)-C^(e2p)-U^(mp)-U^(mp)-T^(e2p)-C^(e2p)-CH₂CH₂OH(AO64)(SEQ ID NO: 67)

The compound of Example 79 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.06min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (9.08 A₂₆₀ units) (λmax (H₂O)=263 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 7.62 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6229.23;measured value: 6229.27).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7907-7924 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 80 Synthesis ofHO-T^(e2p)-T^(e2p)-C^(mp)-T^(e2p)-T^(e2p)-G^(mp)-T^(e2p)-A^(mp)-C^(mp)-T^(e2p)-T^(e2p)-C^(mp)-A^(mp)-T^(e2p)-C^(mp)-C^(e2p)-C^(e2p)-A^(mp)-CH₂CH₂OH(AO65)(SEQ ID NO: 68)

The compound of Example 80 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.16min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (7.19 A₂₆₀ units) (λmax (H₂O)=264 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 7.98 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6188.22;measured value: 6288.69).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7925-7942 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 81 Synthesis ofHO-C^(e2p)-C^(e2p)-U^(mp)-C^(e2p)-C^(e2p)-G^(mp)-G^(mp)-T^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-A^(mp)-G^(mp)-G^(mp)-T^(e2p)-G^(mp)-CH₂CH₂OH(AO66)(SEQ ID NO: 69)

The compound of Example 81 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 5.01min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (10.7 A₂₆₀ units) (λmax (H₂O)=260 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 7.80 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6335.32;measured value: 6334.97).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7943-7960 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 82 Synthesis ofHO-C^(e2p)-A^(mp)-T^(e2p)-T^(e2p)-U^(mp)-C^(e2p)-A^(mp)-U^(mp)-T^(e2p)-C^(e2p)-A^(mp)-A^(mp)-C^(e2p)-T^(e2p)-G^(mp)-T^(e2p)-T^(e2p)-G^(mp)-CH₂CH₂OH(AO67)(SEQ ID NO: 70)

The compound of Example 82 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.36min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (13.8 A₂₆₀ units) (λmax (H₂O)=260 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 6.70 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6252.27;measured value: 6252.37).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7961-7978 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 83 Synthesis ofHO-T^(e2p)-T^(e2p)-C^(mp)-C^(mp)-T^(e2p)-T^(e2p)-A^(mp)-G^(mp)-C^(e2p)-T^(e2p)-U^(mp)-C^(e2p)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-C^(e2p)-A^(mp)-CH₂CH₂OH(AO69)(SEQ ID NO: 71)

The compound of Example 42 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.10min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (8.12 A₂₆₀ units) (λmax (H₂O)=264 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 7.02 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6226.27;measured value: 6226.10).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7997-8014 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 84 Synthesis ofHO-T^(e2p)-A^(mp)-A^(mp)-G^(mp)-A^(mp)-C^(e2p)-C^(e2p)-T^(e2p)-G^(mp)-C^(e2p)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-U^(mp)-T^(e2p)-C^(e2p)-CH₂CH₂OH(AO70)(SEQ ID NO: 72)

The compound of Example 84 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.27min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (12.2 A₂₆₀ units) (λmax (H₂O)=262 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 8.57 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6289.29;measured value: 6289.34).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8015-8032 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 85 Synthesis ofHO-C^(e2p)-T^(e2p)-T^(e2p)-G^(mp)-G^(mp)-C^(e2p)-T^(e2p)-C^(mp)-T^(e2p)-G^(mp)-G^(mp)-C^(mp)-C^(e2p)-T^(e2p)-G^(mp)-U^(mp)-C^(e2p)-C^(e2p)-CH₂CH₂OH(AO71)(SEQ ID NO: 73)

The compound of Example 85 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 5.65min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (10.6 A₂₆₀ units) (λmax (H₂O)=262 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→80% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 5.68 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6274.27;measured value: 6274.42).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8033-8050 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 86 Synthesis ofHO-C^(e2p)-T^(e2p)-C^(mp)-C^(e2p)-T^(e2p)-U^(mp)-C^(e2p)-C^(e2p)-A^(mp)-T^(e2p)-G^(mp)-A^(mp)-C^(e2p)-T^(e2p)-C^(e2p)-A^(mp)-A^(mp)-G^(mp)-CH₂CH₂OH(AO72)(SEQ ID NO: 74)

The compound of Example 86 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→46% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.09min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (10.1 A₂₆₀ units) (λmax (H₂O)=264 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:20%→60% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 8.33 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6249.31;measured value: 6249.21).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8051-8068 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 87 Synthesis ofHO-C^(e2p)-T^(e2p)-G^(mp)-A^(mp)-A^(mp)-G^(mp)-G^(mp)-T^(e2p)-G^(mp)-T^(e2p)-T^(e2p)-C^(e2p)-T^(e2p)-T^(e2p)-G^(mp)-T^(e2p)-A^(mp)-C^(e2p)-CH₂CH₂OH(AO95)(SEQ ID NO: 75)

The compound of Example 87 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.22min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (10.6 A₂₆₀ units) (λmax (H₂O)=259 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:15%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 8.31 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6347.33;measured value: 6347.50).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7934-7951 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 88 Synthesis ofHO-T^(e2p)-T^(e2p)-C^(mp)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-C^(e2p)-A^(mp)-T^(e2p)-T^(e2p)-G^(mp)-T^(e2p)-G^(mp)-T^(e2p)-T^(e2p)-G^(mp)-A^(mp)-CH₂CH₂OH(AO96)(SEQ ID NO: 76)

The compound of Example 88 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 7.09min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (12.8 A₂₆₀ units) (λmax (H₂O)=262 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:15%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 8.60 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6307.31;measured value: 6307.34).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7988-8005 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 89 Synthesis ofHO-C^(e2p)-T^(e2p)-C^(e2p)-A^(mp)-G^(mp)-C^(e2p)-T^(e2p)-U^(mp)-C^(mp)-T^(e2p)-T^(e2p)-C^(mp)-C^(mp)-T^(e2p)-T^(e2p)-A^(mp)-G^(mp)-C^(e2p)-CH₂CH₂OH(AO97)(SEQ ID NO: 77)

The compound of Example 89 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.74min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (10.7 A₂₆₀ units) (λmax (H₂O)=265 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:15%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 8.00 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6203.23;measured value: 6203.08).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8006-8023 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 90 Synthesis ofHO-G^(mp)-C^(e2p)-T^(e2p)-T^(e2p)-C^(mp)-U^(mp)-T^(e2p)-C^(e2p)-C^(mp)-U^(mp)-T^(e2p)-A^(mp)-G^(mp)-C^(e2p)-U^(mp)-T^(e2p)-C^(e2p)-C^(e2p)-CH₂CH₂OH(AO98)(SEQ ID NO: 78)

The compound of Example 90 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 5.35min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (9.81 A₂₆₀ units) (λmax (H₂O)=265 nm). When analyzed byreversed phase HPLC [column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: 25% acetonitrile, 0.1 M TEAA B %:15%→100% (10 min, linear gradient); 60° C.; 2 ml/min; 254 nm], thesubject compound was eluted at 7.06 min. The compound was identified bynegative ion ESI mass spectrometric analysis (calculated value: 6180.19;measured value: 6180.27).

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8002-8019 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 91 Synthesis ofHO-G^(mp)-G^(mp)-C^(e2p)-A^(mp)-T^(e2p)-T^(e2p)-U^(mp)-C^(e2p)-T^(e2p)-A^(mp)-G^(mp)-U^(mp)-T^(e2p)-T^(e2p)-G^(mp)-G^(mp)-A^(e2p)-G^(mp)-CH₂CH₂OH(AO131)(SEQ ID NO: 87)

The compound of Example 91 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.27min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (1.80 A₂₆₀ units). When analyzed by ion exchange HPLC [column:Tosoh TSK-gel DEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile;solution B: 20% acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 MKBr, gradient: solution B 15→60% (10 min, linear gradient); 40° C.; 2ml/min], the subject compound was eluted at 4.89 min.

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7612-7629 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 92 Synthesis ofHO-G^(ms)-G^(ms)-C^(e2s)-A^(ms)-T^(e2s)-T^(e2s)-U^(ms)-C^(e2s)-T^(e2s)-A^(ms)-G^(ms)-U^(ms)-T^(e2s)-T^(e2s)-G^(ms)-G^(ms)-A^(e2s)-G^(ms)-CH₂CH₂OH(AO132)(SEQ ID NO: 87)

The compound of Example 92 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 mixture) for 15 min, instead of theoxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→45% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.47 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (15.1 A₂₆₀units). When analyzed by ion exchange HPLC [column: Tosoh TSK-gelDEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile; solution B: 20%acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 M KBr, gradient:solution B 20→80% (10 min, linear gradient); 40° C.; 2 ml/min], thesubject compound was eluted at 8.46 min.

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7612-7629 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 93 Synthesis ofHO-G^(ms)-C^(e2s)-T^(e2s)-T^(e2s)-C^(ms)-U^(ms)-T^(e2s)-C^(e2s)-C^(ms)-U^(ms)-T^(e2s)-A^(ms)-G^(ms)-C^(e2s)-U^(ms)-T^(e2s)-C^(e2s)-C^(e2s)-CH₂CH₂OH(AO133)(SEQ ID NO: 78)

The compound of Example 93 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 mixture) for 15 min, instead of theoxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→45% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.65 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (15.1 A₂₆₀units). When analyzed by ion exchange HPLC [column: Tosoh TSK-gelDEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile; solution B: 20%acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 M KBr, gradient:solution B 20→80% (10 min, linear gradient); 40° C.; 2 ml/min], thesubject compound was eluted at 6.47 min.

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8002-8019 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 94 Synthesis ofHO-G^(ms)-A^(e2s)-A^(ms)-A^(ms)-A^(ms)-C^(e2s)-G^(ms)-C^(e2s)-C^(e2s)-G^(ms)-C^(ms)-C^(e2s)-A^(ms)-T^(e2s)-U^(ms)-U^(ms)-C^(e2s)-T^(e2s)-CH₂CH₂OH(AO134)(SEQ ID NO: 30)

The compound of Example 94 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 mixture) for 15 min, instead of theoxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→45% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.51 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (6.65 A₂₆₀units). When analyzed by ion exchange HPLC [column: Tosoh TSK-gelDEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile; solution B: 20%acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 M KBr, gradient:solution B 20→80% (10 min, linear gradient); 40° C.; 2 ml/min], thesubject compound was eluted at 7.46 min.

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 6555-6572 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 95 Synthesis ofHO-A^(ms)-C^(e2s)-C^(e2s)-G^(ms)-C^(ms)-C^(e2s)-T^(e2s)-U^(ms)-C^(ms)-C^(e2s)-A^(ms)-C^(ms)-T^(e2s)-C^(e2s)-A^(ms)-G^(ms)-A^(e2s)-G^(ms)-CH₂CH₂OH(AO135)(SEQ ID NO: 41)

The compound of Example 95 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 mixture) for 15 min, instead of theoxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→45% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.87 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (9.06 A₂₆₀units). When analyzed by ion exchange HPLC [column: Tosoh TSK-gelDEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile; solution B: 20%acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 M KBr, gradient:solution B 20→80% (10 min, linear gradient); 40° C.; 2 ml/min], thesubject compound was eluted at 6.92 min.

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7465-7482 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 96 Synthesis ofHO-G^(ms)-C^(e2s)-A^(ms)-G^(ms)-C^(e2s)-C^(e2s)-U^(ms)-C^(ms)-T^(e2s)-C^(ms)-G^(ms)-C^(e2s)-T^(e2s)-C^(ms)-A^(ms)-C^(e2s)-T^(e2s)-C^(ms)-CH₂CH₂OH(AO136)(SEQ ID NO: 47)

The compound of Example 96 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 mixture) for 15 min, instead of theoxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→45% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 6.24 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (11.2 A₂₆₀units). When analyzed by ion exchange HPLC [column: Tosoh TSK-gelDEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile; solution B: 20%acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 M KBr, gradient:solution B 20→80% (10 min, linear gradient); 40° C.; 2 ml/min], thesubject compound was eluted at 6.66 min.

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8275-8292 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 97 Synthesis ofHO-T^(e2s)-C^(e2s)-U^(ms)-U^(ms)-C^(e2s)-C^(e2s)-A^(ms)-A^(ms)-A^(ms)-G^(ms)-C^(e2s)-A^(ms)-G^(ms)-C^(e2s)-C^(ms)-U^(ms)-C^(e2s)-T^(e2s)-CH₂CH₂OH(AO137)(SEQ ID NO: 48)

The compound of Example 97 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 mixture) for 15 min, instead of theoxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→45% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 7.40 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (9.46 A₂₆₀units). When analyzed by ion exchange HPLC [column: Tosoh TSK-gelDEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile; solution B: 20%acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 M KBr, gradient:solution B 20→80% (10 min, linear gradient); 40° C.; 2 ml/min], thesubject compound was eluted at 6.82 min.

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 8284-8301 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 98 Synthesis ofHO-A^(e2s)-G^(ms)-T^(e2s)-U^(ms)-T^(e2s)-G^(ms)-G^(ms)-A^(e2s)-G^(ms)-A^(ms)-T^(e2s)-G^(ms)-G^(ms)-C^(e2s)-A^(e2s)-G^(ms)-T^(e2s)-T^(e2s)-CH₂CH₂OH(AO139)(SEQ ID NO: 88)

The compound of Example 98 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized.However, the portion with a phosphorothioate bond was sulfurized bytreating with a mixed solution of 0.02 M xanthanehydride/acetonitrile-pyridine (9:1 mixture) for 15 min, instead of theoxidation step with iodine-H₂O. After deprotection, the resultantproduct was purified by reversed phase HPLC [Shimadzu model LC-10VP;column: Merck, Chromolith Performance RP-18e (4.6×100 mm); solution A:5% acetonitrile, 0.1 M aqueous triethylamine acetate (TEAA), pH 7.0;solution B: acetonitrile B %: 10%→45% (8 min, linear gradient); 60° C.;2 ml/min; 254 nm]. The fraction eluted at 7.08 min was collected. Afterthe solvent was distilled off under reduced pressure, 80% aqueous aceticacid solution was added to the residue, which was then left for 20 minto remove the DMTr group. After distilling off the solvent, theresultant residue was dissolved in 0.5 ml of water and filtered withUltrafree-MC (Millipore: product No. UFC4 OHV 25). The solvent wasdistilled off to thereby obtain the compound of interest (12.9 A₂₆₀units). When analyzed by ion exchange HPLC [column: Tosoh TSK-gelDEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile; solution B: 20%acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 M KBr, gradient:solution B 20→80% (10 min, linear gradient); 40° C.; 2 ml/min], thesubject compound was eluted at 6.92 min.

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7603-7620 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Example 99 Synthesis ofHO-A^(e2p)-G^(mp)-T^(e2p)-U^(mp)-T^(e2p)-G^(mp)-G^(mp)-A^(e2p)-G^(mp)-A^(mp)-T^(e2p)-G^(mp)-G^(mp)-C^(e2p)-A^(e2p)-G^(mp)-T^(e2p)-T^(e2p)-CH₂CH₂OH(AO140)(SEQ ID NO: 88)

The compound of Example 99 having a sequence of interest was synthesizedin the same manner as the compound of Example 42 was synthesized. Afterdeprotection, the resultant product was purified by reversed phase HPLC[Shimadzu model LC-10VP; column: Merck, Chromolith Performance RP-18e(4.6×100 mm); solution A: 5% acetonitrile, 0.1 M aqueous triethylamineacetate (TEAA), pH 7.0; solution B: acetonitrile B %: 10%→45% (8 min,linear gradient); 60° C.; 2 ml/min; 254 nm]. The fraction eluted at 6.47min was collected. After the solvent was distilled off under reducedpressure, 80% aqueous acetic acid solution was added to the residue,which was then left for 20 min to remove the DMTr group. Afterdistilling off the solvent, the resultant residue was dissolved in 0.5ml of water and filtered with Ultrafree-MC (Millipore: product No. UFC4OHV 25). The solvent was distilled off to thereby obtain the compound ofinterest (3.54 A₂₆₀ units). When analyzed by ion exchange HPLC [column:Tosoh TSK-gel DEAE-5PW (7.5×75 mm); solution A: 20% acetonitrile;solution B: 20% acetonitrile, 67 mM phosphate buffer (pH 6.8), 1.5 MKBr, gradient: solution B 10→50% (10 min, linear gradient); 40° C.; 2ml/min], the subject compound was eluted at 5.54 min.

The nucleotide sequence of the subject compound is complementary to thenucleotides Nos. 7603-7620 of dystrophin cDNA (Gene Bank accession No.NM_(—)004006.1).

Test Example 1 Method of Analysis of the Exon Skipping Induction Abilityby Antisense ENA Preparation of Primary Culture of Myoblast Cells

A primary culture of myoblast cells was established as described below.

1. Muscle tissue samples taken from the rectus muscle of the thigh ofDuchenne muscular dystrophy patients were cut into fine pieces andwashed with PBS twice.2. The muscle tissue from 1 above was treated with Difco Bacto™ tripton250 at 37° C. for 30 min to thereby obtain free cells enzymatically.3. The free cells from 2 above were washed with DMEM (containing 20%FBS) twice.4. The cells from 3 above were suspended in DMEM (containing 20% FBS and4% ultroser G).5. The suspension cells from 4 were passed through a mesh (BectonDickinson: cell strainer 35-2360) to recover only free cells.6. The recovered cells from 5 above were seeded on gelatin-coateddishes.7. The cells were cultured at 37° C. in an atmosphere of 5% CO₂ in air.

Induction of Differentiation

Differentiation of muscular cells was induced as described below.

1. Cultured cells obtained above were seeded on 6-well plates (gelatincoated). When cells became confluent, the medium was exchanged with DMEM(containing 2% horse serum (HS)).2. After a 4 day cultivation, the cells were transfected with thecompounds prepared in Examples (ENAs) as described below.

ENA Transfection

Myoblast cells were transfected with the compounds prepared in Examples(ENAs) as described below.

1. 200 pmol of each of the compounds prepared in Examples (10 μg/20 μlmilliQ) was dissolved in 100 μl of Opti-MEM (GIBCO-BRL).2. 6 μl of Plus reagent (GIBCO-BRL) was added to the solution from 1above, which was then left at room temperature for 15 min.3. In another tube, 8 μl of Lipofectamine (GIBCO-BRL) was dissolved in100 μl of Opti-MEM.4. After completion of the treatment of 2 above, the solution from 3above was added to the solution from 2 above. The resultant solution wasleft at room temperature for another 15 min.5. Myoblast cells 4 days after the start of the induction ofdifferentiation were washed with PBS once. Then, 800 μl of Opti-MEM wasadded thereto.6. After completion of the treatment of 4 above, the treated solutionwas added to the cells from 5 above.7. The cells from 6 above were cultured at 37° C. in an atmosphere of 5%CO₂ in air for 3 hr. Then, 500 μl of DMEM (containing 6% HS) was addedto each well.8. Cells were cultured further.

RNA Extraction

RNA was extracted as described below.

1. ENA-transfected cells were cultured for 2 days and then washed withPBS once. To these cells, 500 μl of ISOGEN (Nippon Gene) was added.2. The cells were left at room temperature for 5 min, followed byrecovery of ISOGEN in each well into tubes.3. RNA was extracted according to the protocol of ISOGEN (Nippon Gene).4. Finally, RNA was dissolved in 20 μl of DEPW.

Reverse Transcription

Reverse transcription was performed as described below.

1. To 2 μg of RNA, DEPW (sterilized water treated withdiethylpyrocarbonate) was added to make a 6 μl solution.2. To the solution from 1 above, 2 μl of random hexamer (Invitrogen: 3μg/μl product was diluted to 20-fold before use) was added.3. The resultant solution was heated at 65° for 10 min.4. Then, the solution was cooled on ice for 2 min.5. To the above reaction solution, the following was added:

MMLV-reverse transcriptase (Invitrogen: 200 U/μl) 1 μl Human placentaribonuclease inhibitor (Takara: 40 U/μl) 1 μl DTT (attached toMMLV-reverse transcriptase) 1 μl Buffer (attached to MMLV-reversetranscriptase) 4 μl dNTPs (attached to Takara Ex Taq) 5 μl6. The resultant solution was kept at 37° C. for 1 hr, and then heatedat 95° C. for 5 min.7. After the reaction, the solution was stored at −80° C.

PCR Reaction

PCR reaction was performed as described below.

1. The following components were mixed and then heated at 94° C. for 4min.

Reverse transcription product 3 μl Forward primer (10 pmol/μl) 1 μlReverse primer (10 pmol/μl) 1 μl dNTP (attached to TAKARA Ex Taq) 2 μlBuffer (attached to TAKARA Ex Taq) 2 μl Ex Taq (TAKARA) 0.1 μl  Sterilized water 11 μl 2. After the above-mentioned treatment at 94° C. for 4 min, 35 cycles of94° C. for 1 min/60° C. for 1 min/72° C. for 3 min were performed.3. Then, the reaction solution was heated at 72° C. for 7 min.

The nucleotide sequences of the forward and reverse primers used in thePCR reaction are as described below.

Forward primer: (SEQ ID NO: 8) GCA TGC TCA AGA GGA ACT TCC (exon 17)Reverse primer: (SEQ ID NO: 9) TAG CAA CTG GCA GAA TTC GAT (exon 20)3. The PCR product was analyzed by 2% agarose gel electrophoresis.

The resultant gel was stained with ethidium bromide. The resultant band(A) (where exon 19 was skipped) and band (B) (where exon 19 was notskipped) were visualized with a gel photographing device (PrintgraphModel AE-6911FXFD; ATTO) and quantitatively determined with ATTODensitograph ver.4.1 for the Macintosh. The values obtained were putinto the formula A/(A+B)×100 to obtain skipping efficiency (%).

5. The band where skipping had occurred was cut out, and the PCR productwas subcloned into pT7 Blue-T vector (Novagen), followed by sequencingreaction with Thermo Sequenase™ II dye terminator cycle sequencing kit(Amersham Pharmacia Biotec) and confirmation of the nucleotide sequencewith ABI PRISM 310 Genetic Analyzer (Applied Biosystems). The reactionprocedures were according to the manual attached to the kit.

[Results]

As shown in FIG. 1 and Table 1, the compound of Example 1 showed moreefficient exon 19 skipping than 31mer-phosphorothioate oligonucleotide(S-oligo) disclosed in Y. Takeshima et al., Brain & Development (2001)23, 788-790, which has the same nucleotide sequence as that of thecompound of Example 1. Further, as shown in FIGS. 2 and 3 and Tables 2and 3, the compounds of Examples 2-14 also showed more efficientskipping than S-oligo.

TABLE 1 Oligonucleotide Skipping (%) S-oligo 2 AO1 Example 1 80

TABLE 2 Oligonucleotide Skipping (%) AO1 Example 1 88 AO14 Example 2 29AO15 Example 3 3 AO16 Example 4 4 AO18 Example 5 92 AO19 Example 6 5AO25 Example 7 83 AO17 Example 13 39 AO24 Example 14 14

TABLE 3 Oligonucleotide Skipping (%) AO18 Example 5 90 AO50 Example 8 53AO51 Example 9 55 AO52 Example 10 97 AO53 Example 11 55 AO54 Example 1291

Test Example 2 Method of Analysis of the Exon Skipping Induction Abilityby Antisense ENA Preparation of Primary Culture of Myoblast Cells

A primary culture of myoblast cells was established as described below.

1. Muscle tissue samples taken from the rectus muscle of the thigh ofDuchenne muscular dystrophy patients were cut into fine pieces andwashed with PBS twice.2. The muscle tissue from 1 above was treated with Difco Bacto™ tripton250 (5% solution in PBS) at 37° C. for 30 min to thereby obtain freecells enzymatically.3. The free cells from 2 above were washed with DMEM (containing 20%FBS) twice.4. The cells from 3 above were suspended in DMEM (containing 20% FBS and4% ultroser G).5. The suspension cells from 4 were passed through a mesh (BectonDickinson: cell strainer 35-2360) to recover only free cells.6. The recovered cells from 5 above were seeded on gelatin-coateddishes.7. The cells were cultured at 37° C. in an atmosphere of 5% CO₂ in air.

Induction of Differentiation

Differentiation of muscular cells was induced as described below.

1. Cultured cells obtained above were seeded on 6-well plates (gelatincoated). When cells became confluent, the medium was exchanged with DMEM(containing 2% horse serum (HS)).2. After a 4 day cultivation, the cells were transfected with thecompounds prepared in Examples (ENAs) as described below.

ENA Transfection

Myoblast cells were transfected with the compounds prepared in Examples(ENAs) as described below.

1. 200 pmol of each of the compounds prepared in Examples (10 μg/20 μlmilliQ) was dissolved in 100 μl of Opti-MEM (GIBCO-BRL).2. 6 μl of Plus reagent (GIBCO-BRL) was added to the solution from 1above, which was then left at room temperature for 15 min.3. In another tube, 8 μl of Lipofectamine (GIBCO-BRL) was dissolved in100 μl of Opti-MEM.4. After completion of the treatment of 2 above, the solution from 3above was added to the solution from 2 above. The resultant solution wasleft at room temperature for another 15 min.5. Myoblast cells 4 days after the start of the induction ofdifferentiation were washed with PBS once. Then, 800 μl of Opti-MEM wasadded thereto.6. After completion of the treatment of 4 above, the treated solutionwas added to the cells from 5 above.7. The cells from 6 above were cultured at 37° C. in an atmosphere of 5%CO₂ in air for 3 hr. Then, 500 μl of DMEM (containing 6% HS) was addedto each well.8. Cells were cultured further.

RNA Extraction

RNA was extracted as described below.

1. ENA-transfected cells were cultured for 2 days and then washed withPBS once. To these cells, 500 μl of ISOGEN (Nippon Gene) was added.2. The cells were left at room temperature for 5 min, followed byrecovery of ISOGEN in each well into tubes.3. RNA was extracted according to the protocol of ISOGEN (Nippon Gene).4. Finally, RNA was dissolved in 20 μl of DEPW.

Reverse Transcription

Reverse transcription was performed as described below.

1. To 2 μg of RNA, DEPW (sterilized water treated withdiethylpyrocarbonate) was added to make a 6 μl solution.2. To the solution from 1 above, 2 μl of random hexamer (Invitrogen: 3μg/μl product was diluted to 20-fold before use) was added.3. The resultant solution was heated at 65° for 10 min.4. Then, the solution was cooled on ice for 2 min.5. To the above reaction solution, the following was added:

MMLV-reverse transcriptase (Invitrogen: 200 U/μl) 1 μl Human placentaribonuclease inhibitor (Takara: 40 U/μl) 1 μl DTT (attached toMMLV-reverse transcriptase) 1 μl Buffer (attached to MMLV-reversetranscriptase) 4 μl dNTPs (attached to Takara Ex Taq) 5 μl6. The resultant solution was kept at 37° C. for 1 hr, and then heatedat 95° C. for 5 min.7. After the reaction, the solution was stored at −80° C.

PCR Reaction

PCR reaction was performed as described below.

1. The following components were mixed and then heated at 94° C. for 4min.

Reverse transcription product 3 μl Forward primer (10 pmol/μl) 1 μlReverse primer (10 pmol/μl) 1 μl dNTP (attached to TAKARA Ex Taq) 2 μlBuffer (attached to TAKARA Ex Taq) 2 μl Ex Taq (TAKARA) 0.1 μl  Sterilized water 11 μl 2. After the above-mentioned treatment at 94° C. for 4 min, 35 cycles of94° C. for 1 min/60° C. for 1 min/72° C. for 3 min were performed.3. Then, the reaction solution was heated at 72° C. for 7 min.

The nucleotide sequences of the forward and reverse primers used in thePCR for detecting exon 41 skipping were as described below.

Forward primer: (SEQ ID NO: 26) 5′-GGT ATC AGT ACA AGA GGC AGGCTG-3′ (exon 40) Reverse primer: (SEQ ID NO: 27) 5′-CAC TTC TAA TAG GGCTTG TG-3′ (exon 42)

The nucleotide sequences of the forward and reverse primers used in thePCR for detecting exon 45 and exon 46 skipping were as described below.

Forward primer: (SEQ ID NO: 28) 5′-GCT GAA CAG TTT CTC AGA AAG ACACAA-3′ (exon 44) Reverse primer: (SEQ ID NO: 29) 5′-TCC ACT GGA GAT TTGTCT GC-3′ (exon 47)4. The PCR product was analyzed by 2% agarose gel electrophoresis.

The resultant gel was stained with ethidium bromide. The resultant band(A) (where an exon was skipped) and band (B) (where an exon was notskipped) were visualized with a gel photographing device (PrintgraphModel AE-6911FXFD; ATTO) and quantitatively determined with ATTODensitograph ver.4.1 for the Macintosh. The values obtained were putinto the formula A/(A+B)×100 to obtain skipping efficiency (%).

5. The band where skipping had occurred was cut out, and the PCR productwas subcloned into pT7 Blue-T vector (Novagen), followed by sequencingreaction with Thermo Sequenase™ II dye terminator cycle sequencing kit(Amersham Pharmacia Biotec) and confirmation of the nucleotide sequencewith ABI PRISM 310 Genetic Analyzer (Applied Biosystems). The reactionprocedures were according to the manual attached to the kit.

[Results]

The results of exon 41 skipping are shown in FIGS. 4 and 5. Exon 41skipping occurred when the compounds of Examples 15 to 25 were used.

The results of exon 45 skipping are shown in FIG. 6. Exon 45 skippingoccurred when the compounds of Examples 26 to 29 were used.

The results of exon 46 skipping are shown in FIGS. 7, 8 and 9. Exon 45skipping occurred when the compounds of Examples 31 to 36 were used.Further, compared to the compound of Reference Example 1 disclosed invan Deutekom, J. C. T. et al. (2001) Hum. Mol. Genet. 10, 1547-1554, thecompound of Example 33 having the same nucleotide sequence showed moreefficient exon 46 skipping. Compared to the compound of ReferenceExample 2 disclosed in van Deutekom, J. C. T. et al. (2001) Hum. Mol.Genet. 10, 1547-1554, the compound of Example 34 having the samenucleotide sequence also showed more efficient exon 46 skipping.Further, compared to the compound of Reference Example 2 disclosed invan Deutekom, J. C. T. et al. (2001) Hum. Mol. Genet. 10, 1547-1554, thecompound of Example 34 having the same nucleotide sequence also showedmore efficient exon 46 skipping. Further, compared to the compound ofReference Example 3 disclosed in van Deutekom, J. C. T. et al. (2001)Hum. Mol. Genet. 10, 1547-1554, the compound of Example 31 having thesame nucleotide sequence also showed more efficient exon 46 skipping.

FIG. 22 shows the results of exon 46 skipping. Exon 46 skipping occurredwhen the compounds of Examples 33 and 37-41 were used.

Test Example 3 Method of Analysis of the Exon Skipping Induction Abilityby Antisense ENA Preparation of Primary Culture of Myoblast Cells

A primary culture of myoblast cells was established as described below.

1. Muscle tissue samples taken from the rectus muscle of the thigh ofDuchenne muscular dystrophy patients were cut into fine pieces andwashed with PBS twice.2. The muscle tissue from 1 above was treated with Difco Bacto™ tripton250 (5% solution in PBS) at 37° C. for 30 min to thereby obtain freecells enzymatically.3. The free cells from 2 above were washed with DMEM (containing 20%FBS) twice.4. The cells from 3 above were suspended in DMEM (containing 20% FBS and4% ultroser G).5. The suspension cells from 4 were passed through a mesh (BectonDickinson: cell strainer 35-2360) to recover only free cells.6. The recovered cells from 5 above were seeded on gelatin-coateddishes.7. The cells were cultured at 37° C. in an atmosphere of 5% CO₂ in air.

Induction of Differentiation

Differentiation of muscular cells was induced as described below.

1. Cultured cells obtained above were seeded on 6-well plates (gelatincoated). When cells became confluent, the medium was exchanged with DMEM(containing 2% horse serum (HS)).2. After a 4 day cultivation, the cells were transfected with thecompounds prepared in Examples (ENAs) as described below.

ENA Transfection

Myoblast cells were transfected with the compounds prepared in Examples(ENAs) as described below.

1. 200 pmol of each of the compounds prepared in Examples (10 μg/20 μlmilliQ) was dissolved in 100 μl of Opti-MEM (GIBCO-BRL).2. 6 μl of Plus reagent (GIBCO-BRL) was added to the solution from 1above, which was then left at room temperature for 15 min.3. In another tube, 8 μl of Lipofectamine (GIBCO-BRL) was dissolved in100 μl of Opti-MEM.4. After completion of the treatment of 2 above, the solution from 3above was added to the solution from 2 above. The resultant solution wasleft at room temperature for another 15 min.5. Myoblast cells 4 days after the start of the induction ofdifferentiation were washed with PBS once. Then, 800 μl of Opti-MEM wasadded thereto.6. After completion of the treatment of 4 above, the treated solutionwas added to the cells from 5 above.7. The cells from 6 above were cultured at 37° C. in an atmosphere of 5%CO₂ in air for 3 hr. Then, 500 μl of DMEM (containing 6% HS) was addedto each well.8. Cells were cultured further.

RNA Extraction

RNA was extracted as described below.

1. ENA-transfected cells were cultured for 2 days and then washed withPBS once. To these cells, 500 μl of ISOGEN (Nippon Gene) was added.2. The cells were left at room temperature for 5 min, followed byrecovery of ISOGEN in each well into tubes.3. RNA was extracted according to the protocol of ISOGEN (Nippon Gene).4. Finally, RNA was dissolved in 20 μl of DEPW.

Reverse Transcription

Reverse transcription was performed as described below.

1. To 2 μg of RNA, DEPW (sterilized water treated withdiethylpyrocarbonate) was added to make a 6 μl solution.2. To the solution from 1 above, 2 μl of random hexamer (Invitrogen: 3μg/μl product was diluted to 20-fold before use) was added.3. The resultant solution was heated at 65° for 10 min.4. Then, the solution was cooled on ice for 2 min.5. To the above reaction solution, the following was added:

MMLV-reverse transcriptase (Invitrogen: 200 U/μl) 1 μl Human placentaribonuclease inhibitor (Takara: 40 U/μl) 1 μl DTT (attached toMMLV-reverse transcriptase) 1 μl Buffer (attached to MMLV-reversetranscriptase) 4 μl dNTPs (attached to Takara Ex Taq) 5 μl6. The resultant solution was kept at 37° C. for 1 hr, and then heatedat 95° C. for 5 min.7. After the reaction, the solution was stored at −80° C.

PCR Reaction

PCR reaction was performed as described below.

1. The following components were mixed and then heated at 94° C. for 4min.

Reverse transcription product 3 μl Forward primer (10 pmol/μl) 1 μlReverse primer (10 pmol/μl) 1 μl dNTP (attached to TAKARA Ex Taq) 2 μlBuffer (attached to TAKARA Ex Taq) 2 μl Ex Taq (TAKARA) 0.1 μl  Sterilized water 11 μl 2. After the above-mentioned treatment at 94° C. for 4 min, 35 cycles of94° C. for 1 min/60° C. for 1 min/72° C. for 3 min were performed.3. Then, the reaction solution was heated at 72° C. for 7 min.

The nucleotide sequences of the forward and reverse primers used in thePCR reactions for detecting the skipping of exons 44, 50, 51, 53 and 55are as described below. Exon 44:

Exon 44: Forward: (SEQ ID NO: 79) 5′-TAGTCTACAACAAAGCTCAGGT-3′ (exon 43)Reverse: (SEQ ID NO: 80) 5′-CTTCCCCAGTTGCATTCAAT-3′ (exon 45) Exons 50and 51: Forward: (SEQ ID NO: 81) 5′-CAAGGAGAAATTGAAGCTCAA-3′ (exon 48)Reverse: (SEQ ID NO: 82) 5′-CGATCCGTAATGATTGTTCTAGC-3′ (exon 52) Exon53: Forward: (SEQ ID NO: 83) 5′-TGGACAGAACTTACCGACTGG-3′ (exon 51)Reverse: (SEQ ID NO: 84) 5′-GGCGGAGGTCTTTGGCCAAC-3′ (exon 54) Exon 55:Forward: (SEQ ID NO: 85) 5′-AAGGATTCAACACAATGGCTGG-3′ (exon 53) Reverse:(SEQ ID NO: 86) 5′-GTAACAGGACTGCATCATCG-3′ (exon 56)3. The PCR product was analyzed by 2% agarose gel electrophoresis.

The resultant gel was stained with ethidium bromide. The resultant band(A) (where an exon was skipped) and band (B) (where an exon was notskipped) were visualized with a gel photographing device (PrintgraphModel AE-6911FXFD; ATTO) and quantitatively determined with ATTODensitograph ver.4.1 for the Macintosh. The values obtained were putinto the formula A/(A+B)×100 to obtain skipping efficiency (%).

5. The band where skipping had occurred was cut out, and the PCR productwas subcloned into pT7 Blue-T vector (Novagen), followed by sequencingreaction with Thermo Sequenase™ II dye terminator cycle sequencing kit(Amersham Pharmacia Biotec) and confirmation of the nucleotide sequencewith ABI PRISM 310 Genetic Analyzer (Applied Biosystems). The reactionprocedures were according to the manual attached to the kit.

[Results]

FIGS. 10 and 11 show examples of exon 44 skipping induced by compoundsA0100, AO102-106 and AO124-127. As shown in these Figures, exon 44skipping was observed when these compounds were used.

FIGS. 12 and 13 show examples of exon 50 skipping induced by compoundsAO108-113 and AO128. In FIG. 13, assay was performed under conditionsthat the concentration of the compounds was 40 pmol/ml. As shown inthese Figures, exon 50 skipping was observed when these compounds wereused.

FIGS. 14, 15, 16 and 17 shows examples of exon 51 skipping induced bycompounds A03-6, AO8-10, AO37, AO39, AO43 and AO58. As shown in theseFigures, exon 51 skipping was observed when these compounds were used.

FIGS. 18 and 19 show examples of exon 53 skipping induced by compoundsA064-67, AO69-72 and AO95-98. As shown in these Figures, exon 53skipping was observed when these compounds were used.

FIGS. 20 and 21 show examples of exon 44 skipping induced by compoundsA0114-116, AO118-120, AO122, AO123 and AO129. In FIG. 21, assay wasperformed under conditions that the concentration of the compounds was100 pmol/ml. As shown in these Figures, exon 44 skipping was observedwhen these compounds were used.

Formulation Example 1

According to the following prescription, necessary amounts of basecomponents are mixed and dissolved. To this solution, any one of thecompounds of Examples 1 to 99 or a salt thereof is dissolved to preparea solution of a specific volume. The resultant solution is filtered witha membrane filter 0.22 μm in pore size to thereby obtain a preparationfor intravenous administration.

Any one of the compounds of Examples 1 to 99 or a 500 mg salt thereofSodium chloride 8.6 g Potassium chloride 0.3 g Calcium chloride 0.33 gDistilled water for injection to give a total volume of 1000 ml

Formulation Example 2

According to the following prescription, necessary amounts of basecomponents are mixed and dissolved. To this solution, any one of thecompounds of Examples 1 to 99 or a salt thereof is dissolved to preparea solution of a specific volume. The resultant solution is filtered witha filter 15 nm in pore size (PLANOVE 15: Asahi Kasei) to thereby obtaina preparation for intravenous administration.

Any one of the compounds of Examples 1 to 99 or a 100 mg salt thereofSodium chloride 8.3 g Potassium chloride 0.3 g Calcium chloride 0.33 gSodium hydrogenphosphate•12H₂O 1.8 g 1N HCl appropriate amount (pH 7.4)Distilled water for injection to give a total volume of 1000 ml

Formulation Example 3

According to the following prescription, necessary amounts of basecomponents are mixed and dissolved. To this solution, any one of thecompounds of Examples 1 to 99 or a salt thereof is dissolved to preparea solution of a specific volume. The resultant solution is filtered witha filter 35 nm in pore size (PLANOVE 35: Asahi Kasei) to thereby obtaina preparation for intravenous administration.

Any one of the compounds of Examples 1 to 99 or a 100 mg salt thereofSodium chloride 8.3 g Potassium chloride 0.3 g Calcium chloride 0.33 gGlucose 0.4 g Sodium hydrogenphosphate•12H₂O 1.8 g 1N HCl appropriateamount (pH 7.4) Distilled water for injection to give a total volume of1000 ml

All publications, patents and patent applications cited herein areincorporated herein by reference in their entity.

INDUSTRIAL APPLICABILITY

The compounds of the present invention and pharmacologically acceptablesalts thereof have an effect of inducing skipping of exon 19, 41, 45,46, 44, 50, 55, 51 or 53 of the dystrophin gene and thus useful aspharmaceuticals for treating muscular dystrophy.

SEQUENCE LISTING FREE TEXT

SEQ ID NO: 1 shows the nucleotide sequence of the oligonucleotideprepared in Example 1 (AO1).

SEQ ID NO: 2 shows the nucleotide sequence of the oligonucleotidesprepared in Examples 2 and 14 (AO14 and AO24).

SEQ ID NO: 3 shows the nucleotide sequence of the oligonucleotideprepared in Example 3 (AO15).

SEQ ID NO: 4 shows the nucleotide sequence of the oligonucleotideprepared in Example 5 (AO18) and the oligonucleotide prepared in Example7 (AO25).

SEQ ID NO: 5 shows the nucleotide sequence of the oligonucleotideprepared in Example 6 (AO19).

SEQ ID NO: 6 shows the nucleotide sequence of the oligonucleotideprepared in Example 4 (AO16).

SEQ ID NO: 7 shows the nucleotide sequence of the oligonucleotideprepared in Example 13 (AO17).

SEQ ID NO: 8 shows the nucleotide sequence of the forward primer used inTest Example 1.

SEQ ID NO: 9 shows the nucleotide sequence of the reverse primer used inTest Examples 1.

SEQ ID NO: 10 shows the nucleotide sequence of the oligonucleotidesprepared in Examples 15 and 16 (AO20 and AO26).

SEQ ID NO: 11 shows the nucleotide sequence of the oligonucleotideprepared in Example 17 (AO55).

SEQ ID NO: 12 shows the nucleotide sequence of the oligonucleotidesprepared in Examples 18, 20, 21 and 22 (AO56, AO76, AO77 and AO78).

SEQ ID NO: 13 shows the nucleotide sequence of the oligonucleotidesprepared in Examples 19, 23, 24 and 25 (AO57, AO79, AO80 and AO81) andthe oligonucleotide prepared in Example 21 (AO25).

SEQ ID NO: 14 shows the nucleotide sequence of the oligonucleotideprepared in Example 26 (AO33).

SEQ ID NO: 15 shows the nucleotide sequence of the oligonucleotidesprepared in Examples 27 and 30 (AO85 and SO88).

SEQ ID NO: 16 shows the nucleotide sequence of the oligonucleotideprepared in Example 28 (AO86).

SEQ ID NO: 17 shows the nucleotide sequence of the oligonucleotideprepared in Example 29 (AO87).

SEQ ID NO: 18 shows the nucleotide sequence of the oligonucleotideprepared in Example 31 (AO2).

SEQ ID NO: 19 shows the nucleotide sequence of the oligonucleotidesprepared in Examples 32 and 35 (AO23 and AO29).

SEQ ID NO: 20 shows the nucleotide sequence of the oligonucleotideprepared in Example 36 (AO48).

SEQ ID NO: 21 shows the nucleotide sequence of the oligonucleotidesprepared in Examples 33, 37, 38, 39, 40 and 41 (AO27, AO89, AO90, SO91,AO92 and AO93).

SEQ ID NO: 22 shows the nucleotide sequence of the oligonucleotideprepared in Example 34 (AO28).

SEQ ID NO: 23 shows the nucleotide sequence of the oligonucleotideprepared in Reference Example 1.

SEQ ID NO: 24 shows the nucleotide sequence of the oligonucleotideprepared in Reference Example 2.

SEQ ID NO: 25 shows the nucleotide sequence of the oligonucleotideprepared in Reference Example 3.

SEQ ID NO: 26 shows the nucleotide sequence of the forward primer (forthe PCR reaction for detecting exon 41 skipping) used in Test Example 2.

SEQ ID NO: 27 shows the nucleotide sequence of the reverse primer (forthe PCR reaction for detecting exon 41 skipping) used in Test Example 2.

SEQ ID NO: 28 shows the nucleotide sequence of the forward primer (forthe PCR reaction for detecting exon 45 and exon 46 skipping) used inTest Example 2.

SEQ ID NO: 29 shows the nucleotide sequence of the reverse primer (forthe PCR reaction for detecting exon 45 and exon 46 skipping) used inTest Example 2.

SEQ ID NO: 30 shows the nucleotide sequence of the oligonucleotidesprepared in Examples 42 and 94 (AO100 and AO134).

SEQ ID NO: 31 shows the nucleotide sequence of the oligonucleotideprepared in Example 43 (AO102).

SEQ ID NO: 32 shows the nucleotide sequence of the oligonucleotideprepared in Example 44 (AO103).

SEQ ID NO: 33 shows the nucleotide sequence of the oligonucleotideprepared in Example 45 (AO104).

SEQ ID NO: 34 shows the nucleotide sequence of the oligonucleotideprepared in Example 46 (AO105).

SEQ ID NO: 35 shows the nucleotide sequence of the oligonucleotideprepared in Example 47 (AO106).

SEQ ID NO: 36 shows the nucleotide sequence of the oligonucleotideprepared in Example 62 (AO124).

SEQ ID NO: 37 shows the nucleotide sequence of the oligonucleotideprepared in Example 63 (AO125).

SEQ ID NO: 38 shows the nucleotide sequence of the oligonucleotideprepared in Example 64 (AO126).

SEQ ID NO: 39 shows the nucleotide sequence of the oligonucleotideprepared in Example 65 (AO127).

SEQ ID NO: 40 shows the nucleotide sequence of the oligonucleotideprepared in Example 48 (AO108).

SEQ ID NO: 41 shows the nucleotide sequence of the oligonucleotidesprepared in Examples 49 and 95 (AO109 and AO135).

SEQ ID NO: 42 shows the nucleotide sequence of the oligonucleotideprepared in Example 50 (AO110).

SEQ ID NO: 43 shows the nucleotide sequence of the oligonucleotideprepared in Example 51 (AO111).

SEQ ID NO: 44 shows the nucleotide sequence of the oligonucleotideprepared in Example 52 (AO112).

SEQ ID NO: 45 shows the nucleotide sequence of the oligonucleotideprepared in Example 53 (AO113).

SEQ ID NO: 46 shows the nucleotide sequence of the oligonucleotideprepared in Example 66 (AO128).

SEQ ID NO: 47 shows the nucleotide sequence of the oligonucleotidesprepared in Examples 54 and 96 (AO114 and SO136).

SEQ ID NO: 48 shows the nucleotide sequence of the oligonucleotidesprepared in Example 55 and 97 (AO115 and AO137).

SEQ ID NO: 49 shows the nucleotide sequence of the oligonucleotideprepared in Example 56 (AO116).

SEQ ID NO: 50 shows the nucleotide sequence of the oligonucleotideprepared in Example 57 (AO118).

SEQ ID NO: 51 shows the nucleotide sequence of the oligonucleotideprepared in Example 58 (AO119).

SEQ ID NO: 52 shows the nucleotide sequence of the oligonucleotideprepared in Example 59 (AO120).

SEQ ID NO: 53 shows the nucleotide sequence of the oligonucleotideprepared in Example 60 (AO122).

SEQ ID NO: 54 shows the nucleotide sequence of the oligonucleotideprepared in Example 61 (AO123).

SEQ ID NO: 55 shows the nucleotide sequence of the oligonucleotideprepared in Example 67 (AO129).

SEQ ID NO: 56 shows the nucleotide sequence of the oligonucleotideprepared in Example 68 (AO3).

SEQ ID NO: 57 shows the nucleotide sequence of the oligonucleotideprepared in Example 69 (AO4).

SEQ ID NO: 58 shows the nucleotide sequence of the oligonucleotideprepared in Example 70 (AO5).

SEQ ID NO: 59 shows the nucleotide sequence of the oligonucleotideprepared in Example 71 (AO6).

SEQ ID NO: 60 shows the nucleotide sequence of the oligonucleotideprepared in Example 72 (AO8).

SEQ ID NO: 61 shows the nucleotide sequence of the oligonucleotideprepared in Example 73 (AO9).

SEQ ID NO: 62 shows the nucleotide sequence of the oligonucleotideprepared in Example 74 (AO10).

SEQ ID NO: 63 shows the nucleotide sequence of the oligonucleotideprepared in Example 75 (AO37).

SEQ ID NO: 64 shows the nucleotide sequence of the oligonucleotideprepared in Example 76 (AO39).

SEQ ID NO: 65 shows the nucleotide sequence of the oligonucleotideprepared in Example 77 (AO43).

SEQ ID NO: 66 shows the nucleotide sequence of the oligonucleotideprepared in Example 78 (AO58).

SEQ ID NO: 67 shows the nucleotide sequence of the oligonucleotideprepared in Example 79 (AO64).

SEQ ID NO: 68 shows the nucleotide sequence of the oligonucleotideprepared in Example 80 (AO65).

SEQ ID NO: 69 shows the nucleotide sequence of the oligonucleotideprepared in Example 81 (AO66).

SEQ ID NO: 70 shows the nucleotide sequence of the oligonucleotideprepared in Example 82 (AO67).

SEQ ID NO: 71 shows the nucleotide sequence of the oligonucleotideprepared in Example 83 (AO69).

SEQ ID NO: 72 shows the nucleotide sequence of the oligonucleotideprepared in Example 84 (AO70).

SEQ ID NO: 73 shows the nucleotide sequence of the oligonucleotideprepared in Example 85 (AO71).

SEQ ID NO: 74 shows the nucleotide sequence of the oligonucleotideprepared in Example 86 (AO72).

SEQ ID NO: 75 shows the nucleotide sequence of the oligonucleotideprepared in Example 87 (AO95).

SEQ ID NO: 76 shows the nucleotide sequence of the oligonucleotideprepared in Example 88 (AO96).

SEQ ID NO: 77 shows the nucleotide sequence of the oligonucleotideprepared in Example 89 (AO97).

SEQ ID NO: 78 shows the nucleotide sequence of the oligonucleotidesprepared in Examples 90 and 93 (AO98 and AO133).

SEQ ID NO: 79 shows the nucleotide sequence of the forward primer (forthe PCR reaction for detecting exon 44 skipping) used in Test Example 3.

SEQ ID NO: 80 shows the nucleotide sequence of the reverse primer (forthe PCR reaction for detecting exon 44 skipping) used in Test Example 3.

SEQ ID NO: 81 shows the nucleotide sequence of the forward primer (forthe PCR reaction for detecting exon 50 and exon 51 skipping) used inTest Example 3.

SEQ ID NO: 82 shows the nucleotide sequence of the reverse primer (forthe PCR reaction for detecting exon 50 and exon 51 skipping) used inTest Example 3.

SEQ ID NO: 83 shows the nucleotide sequence of the forward primer (forthe PCR reaction for detecting exon 53 skipping) used in Test Example 3.

SEQ ID NO: 84 shows the nucleotide sequence of the reverse primer (forthe PCR reaction for detecting exon 53 skipping) used in Test Example 3.

SEQ ID NO: 85 shows the nucleotide sequence of the forward primer (forthe PCR reaction for detecting exon 55 skipping) used in Test Example 3.

SEQ ID NO: 86 shows the nucleotide sequence of the reverse primer (forthe PCR reaction for detecting exon 55 skipping) used in Test Example 3.

SEQ ID NO: 87 shows the nucleotide sequence of the oligonucleotidesprepared in Example 91 and 92 (AO131 and AO132).

SEQ ID NO: 88 shows the nucleotide sequence of the oligonucleotidesprepared in Example 98 and 99 (AO139 and AO140).

1. (canceled)
 2. An oligonucleotide having the nucleotide sequence asshown in any one of SEQ ID NOS: 18-22, 30, 41, 64, 66, or 87 in theSEQUENCE LISTING, or a pharmacologically acceptable salt thereof.
 3. Theoligonucleotide of claim 2, wherein the oligonucleotide has thenucleotide sequence as shown in SEQ ID NO: 18 in the SEQUENCE LISTING,or a pharmacologically acceptable salt thereof.
 4. The oligonucleotideof claim 2, wherein the oligonucleotide has the nucleotide sequence asshown in SEQ ID NO: 19 in the SEQUENCE LISTING, or a pharmacologicallyacceptable salt thereof.
 5. The oligonucleotide of claim 2, wherein theoligonucleotide has the nucleotide sequence as shown in SEQ ID NO: 20 inthe SEQUENCE LISTING, or a pharmacologically acceptable salt thereof. 6.The oligonucleotide of claim 2, wherein the oligonucleotide has thenucleotide sequence as shown in SEQ ID NO: 21 in the SEQUENCE LISTING,or a pharmacologically acceptable salt thereof.
 7. The oligonucleotideof claim 2, wherein the oligonucleotide has the nucleotide sequence asshown in SEQ ID NO: 22 in the SEQUENCE LISTING, or a pharmacologicallyacceptable salt thereof.
 8. The oligonucleotide of claim 2, wherein theoligonucleotide has the nucleotide sequence as shown in SEQ ID NO: 30 inthe SEQUENCE LISTING, or a pharmacologically acceptable salt thereof. 9.The oligonucleotide of claim 2, wherein the oligonucleotide has thenucleotide sequence as shown in SEQ ID NO: 41 in the SEQUENCE LISTING,or a pharmacologically acceptable salt thereof.
 10. The oligonucleotideof claim 2, wherein the oligonucleotide has the nucleotide sequence asshown in SEQ ID NO: 64 in the SEQUENCE LISTING, or a pharmacologicallyacceptable salt thereof.
 11. The oligonucleotide of claim 2, wherein theoligonucleotide has the nucleotide sequence as shown in SEQ ID NO: 66 inthe SEQUENCE LISTING, or a pharmacologically acceptable salt thereof.12. The oligonucleotide of claim 2, wherein the oligonucleotide has thenucleotide sequence as shown in SEQ ID NO: 87 in the SEQUENCE LISTING,or a pharmacologically acceptable salt thereof.